Open access peer-reviewed chapter

Major Components in Limiting Litter Size

Written By

María-José Argente

Submitted: May 25th, 2015 Reviewed: January 22nd, 2016 Published: March 23rd, 2016

DOI: 10.5772/62280

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Abstract

The litter size is an important trait in prolific species such as rabbits and pigs. However, selection on litter size has had limited success in these species because of its low heritability and sex-limited expression. The litter size is a complex physiological trait in prolific species, affected by several components that are expressed sequentially, for example, ovulation, fertilization, embryo development, and fetal survival. The selection for ovulation rate or/and prenatal survival has been proposed to improve litter size indirectly. However, these alternative methods have not reached the expected response rate. Implantation is also a critical point in successful gestation, one-third to one-half of prenatal mortality occurring during peri-implantation. The uterus must provide an adequate microenviroment for the growth and development of embryo and for receptivity to implantation. There are multitudes of cellular events involved in crosstalk between embryo and maternal uterus during peri-implantation. A better understanding of molecular mechanisms affecting the implantation process could help to propose new strategies for litter size improvement in prolific species.

Keywords

  • Ovulation rate
  • embryonic survival
  • litter size
  • candidate gene
  • quantitative trait loci (QTL)

1. Introduction

Litter size is a complex physiological trait in prolific species, being affected by several component traits representing sequential events, e.g., ovulation, fertilization, embryo development, and fetal survival. Fertilization rate is usually high, exceeding 90 to 95% in rabbit [1], pigs [2], and mice [3]. Therefore, prenatal survival is considered a limiting factor of litter size. Uterine capacity is an important component in prenatal survival [4; for a review address to 5]. Whenever the ovulation is not a limiting factor, this trait depicts the ability of the uterus to support embryo development through gestation [6]. Approximately 30 to 40% of ova shed do not result in fetuses at term in prolific species such as rabbits, pigs, and mice (see review [7]) due to potentially viable embryos exceeds uterine capacity. One-third to one-half of these losses occurs during peri-implantation in rabbits [8], pigs [9], and mice [10]. Preimplantation embryo losses are mainly associated with embryonic viability [4], including chromosomal abnormalities [11] and oviductal or uterine environment, particularly in relation with the suitability of oviductal or uterine secretions [12]. The oviduct must provide an adequate milieu for sperm capacitation, gamete fertilization, and the first embryo cleavages until the embryo enters the uterus [13]. Many proteins that may contribute to these functions have been identified in the oviduct, including the insulin-like growth factor 1 (IGF1) [14], oviductin (OVGP1, known also as MUC9) [15], tissue inhibitor of metalloproteinase (TIMP1) [16], plasminogen activator inhibitor 1 (PAI1) [17], uteroglobin [18], and leptin [19]. A progesterone-primed uterus coordinates the embryo survival and receptivity. The asynchrony between embryo development and uterine environment increases the number of dead embryos in the peri-implantation gestational stage [20, 21].

In rabbits, the period between pregnancy days 8 to 17 is critical for fetal survival, corresponding to the stage when the hemochorial placenta of rabbit is established and the control of the fetal nutrition is transferred to the placenta [22]. A secondary critical period for fetal survival occurs between pregnancy days 17 and 24, accompanying the uterine enlargement, the increased tension exerted on the spherical conceptus, and the reduction of blood flowing through the maternal vessels of the uterus [23]. In this moment, the placenta should compensate these limiting factors and increase its surface area for fetomaternal exchanges [24] and stimulate the development of an adequate vascular network [25, 26]. In pigs, the distribution of mortality after implantation is slightly different throughout pregnancy [9], the first peak occurring between days 30 and 40 of gestation (10-15%) while the second peak is observed in the last two weeks of gestation (5-10%). Despite the existing species differences, it is now accepted that each embryo requires a minimum space in uterus to attach, survive, and develop. Thus, a decrease in the availability of uterine space increases prenatal mortality in pluriparous species, such as rabbits [4] or pigs [27], despite that the factors involved in the process may differ among species. In pigs, the area of attachment between the placenta and endometrium is a limiting factor of uterine capacity, due to its noninvasive placentation [9]. Thus, it was proposed that uterine capacity in pigs could be defined more correctly as the total amount of placental mass or surface area that a dam can support to term [28]. Earlier studies in pigs indicate that the limiting influence of the uterine capacity is generally exerted after the day 30 of gestation and that the effects of moderate crowding of embryos before day 30 could be compensated by increased placental efficiency later in gestation (see review [29]).

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2. Selection experiments for components of litter size

Litter size is an important economic trait in prolific species such as rabbits or pigs. However, direct selection for litter size has not presented the success expected for these species (see review [7, 30]), which may be due to the fact that it is a female sex-limited trait with low heritability. The selection response for litter size has been established around 0.1 young per generation in rabbits [31, 32] and pigs [33-36]. This response has been much lower than that reported in mice: 0.15 to 0.20 young per generation [37-40]. Recently, in pigs, a selection experiment for litter size at day 5 after farrowing obtained a selection response around to 0.25 young per generation [41]. However, additional information on following generations will be required to confirm this trend.

The leading components of litter size are the ovulation rate and the prenatal survival; these parameters are also the limiting factors for the litter size improvement. For this reason, selection for ovulation rate and prenatal survival has been proposed as an indirect approach for increasing litter size. Selection for ovulation rate in prolific species, namely rabbits [42], pigs [43-45], and mice [40, 46], were in fact successful to improve the ovulation rate, but it was not convoyed by a corresponding increase in litter size in either pigs or rabbits, which was attributed to an increase in prenatal loss.

The selection for prenatal survival in pigs [45] and mice [40] allowed to increase litter size in both pigs and mice, but it was not more advantageous compared with the direct selection for litter size. Besides, prenatal survival might be limited by uterine capacity, defined as the maximum number of fetuses that a dam can support at birth when ovulation rate is not a limiting factor [6]. However, the ability to establish this trait is not easily performed across species, as it is dependent on the species physiology. In pigs, litter size in unilaterally ovario-hysterectomized females may be considered an indirect measure of the uterine capacity in pigs [6], since the remaining ovary nearly doubled its ovulation rate originating the fetal overcrowding in the ipsilateral uterine horn. Conversely, in unilaterally ovariectomized female rabbits and mice, which possess a duplex uterus that impedes intercornual transmigration, the number of total fetuses would represent their uterine capacity [47, 48].

Selection experiments for increased uterine capacity failed to obtain the expected success on litter size, in rabbits [8, 49], pigs [44], or mice [50]. Considering that uterine capacity in pigs would be more appropriately measured using the total amount of placental mass or the surface area that a dam can support to term as variables [28], a divergent selection experiment for placental efficiency developed in this species achieved success [51]. However, selection for increased placental efficiency will unlikely result in correlated increase in litter size [52].

A joint selection for ovulation rate and prenatal survival using an index would expectably show a greater response on litter size, since these parameters are optimally weighted [53, 54]. In pigs [55] and mice [56], the use of this joint selection successfully increased litter size, but the gain was lower than expected, probably due to a low precision of the estimated genetic correlations or the use of inappropriate economic weights [57]. Alternatively, a two-stage selection was proposed, which would be less affected by the precision of the genetic parameters; its application to rabbits [58] and pigs [59] obtained greater response on litter size than the observed in the other experiments of selection for litter size [31-36].

Selection for the environmental variability in litter size has been recently proposed as an alternative method for increased litter size. A reduction in litter size environmental variability would increase litter size heritability, and consequently its response to selection [60]. In rabbits, the environmental variance of a doe was estimated as within-doe variance of litter size. Selection for environmental variance of litter size was successful [61], and as a consequence of reducing litter size variability the litter size was increased due to higher embryo survival [61].

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3. Genetic control before implantation

The maternal genome controls virtually all aspects of early embryo development, through several maternal gene products such as mRNA and protein, which are loaded into the egg during oogenesis. As development proceeds, two processes subsequently lead to the maternal-to-zygotic transition (MZT) during which developmental control is transferred to the zygotic genome: first, a subset of the maternal mRNAs is degraded; second, the embryonic genome is transcriptionally activated. These maternal gene products play an important role in the regulation of the first cleavages until embryonic genome is activated [62]. Zygotic genome activation (ZGA) is a critical event determining the transition from maternal to embryonic control of development. Disruption of these critical events by specific chemicals or environmental factors results in irreversible arrest of embryo development [63]. ZGA has been shown to be a species-specific phenomenon, occurring at 2-cell stage in mice [64], 4-cell stage in pigs [65], and 8- to 16- cell stages in sheep, cows, or rabbits [66]. Many maternal-effect genes have been identified initially in mouse during the MZT, and several of whom have been detected posteriorly in rabbits and pigs.

Genome-wide gene activation in the zygote (ZGA) is regarded as crucial for preimplantation embryonic development. Multiple maternal factors were identified on the regulation of ZGA, which are listed in Table 1. Ablation of the gene encoding for these proteins results in embryonic arrest at cleavage-stage development.

Symbol gene Name Effect References in
Mice* Rabbits and pigs
DICER1 Endoribonuclease Dicer or helicase with RNase motif Metaphase II [67] [68]
HSF1 Heat shock factor 1 Zygote [69] [70]
UCHL1 Ubiquitin carboxyl-terminal hydrolase L1 Zygote [71] [72]
AGO2 Argonaute 2 Zygote [73] [75]
MATER or NLRP5 Maternal antigen that embryos require 2-cell stage [75] [76]
ZAR1 Zygote arrest 1 2-cell stage [77] [78]
PADI6 Peptidylarginine deiminase type 6 2-cell stage [79] [80]
SEBOX Skin-embryo-brain-oocyte homeobox 2-cell stage [81] [82]
BRG1 or SMARCA4 Brahma-related gene 1 4-cell stage [83] [84]
DNMT1 DNA cytosine methyltransferase 1 4-cell stage [85] [86]
DNMT3A DNA cytosine methyltransferase 3 alpha 4-cell stage [87] [86]
TET1, 2 and 3 Ten-eleven translocation (Tet) dioxygenases 4-cell stage [88]
KLF4 Kruppel-like factor 4 4-cell stage [89, 90]
BCLXL B-cell lymphoma-extra large 8-cell stage [89]
HDAC1 Histone deacetylase 1 8-cell stage [89]
C-MYC Avian myelocytomatosis viral oncogene homolog 8-cell stage [90]
NANOG The homeoprotein Nanog 16-cell stage [91] [84, 89, 93]
OCT4 or POU5F1 Octamer-binding protein 4 Morula [92] [89, 90, 93]
SOX2 SRY-box containing gene 2 Blastocyst [84, 89, 93]

Table 1.

Maternal genes acting on early fetal embryogenesis.

* Using gene-knockout mouse models.


These factors play critical roles in the regulation of embryo preimplantation development. For example, DICER1 enzyme is required for completion of oocyte mitotic maturation, and oocytes are arrested in metaphase of meiosis II when DICER1 gene is deleted [67, 68]. HSF1 protein is required for oocyte maturation. Embryos produced in knockout females for this gene are unable to proceed into the 2-cell stage after fertilization, possibly due to mitochondrial damage and altered redox homeostasis [69, 70]. UCHL1 is an import factor in blocking polyspermy [71, 72]. AGO2 is involved in the destruction of maternally inherited transcripts and activation of zygotic gene expression; knockout female for this factor is infertile because embryos fail to undergo the first cleavage [73, 74]. Moreover, embryos from MATER, ZAR1, PADI6, and SEBOX knockout females do not develop beyond the 2-cell stage embryo [75-82], and embryos lacking SMARCA4, DNMT1, DNMT3A, TET, and KLF4 are unable to reach the 8-cell stage [83-91]. BCLXL, HDAC1, and C-MYC exhibit maximum expression in 8-cell rabbit embryos coinciding with start of ZGA [90]. Hence the peak expression of transcripts at ZGA might be a requirement for embryo development. OCT4, NANOG, and SOX2 were co-expressed in epiblasts, and the combinatorial expression of these three genes is critical for the embryo development [92, 93].

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4. Genetic control during implantation

Implantation requires a complex interaction among the developing embryo, decidualizing endometrium and developing maternal immune tolerance. For the successful implantation, it is of upmost importance the synchronization between the acquisition of implantation competency by the blastocyst and a receptive state in the uterine endometrium, for which the concurrence of the ovarian steroid hormones dynamics is crucial. The ovarian hormones determine a complex interplay of locally produced molecules in the endometrium, including cytokines, growth factors, homeobox transcription factors, lipid mediators, and morphogen genes that are involved in the complex process of implantation. The crosstalk between the blastocyst and the uterus is limited in most mammal species for a brief period, named as window of implantation. During this short period, in response to a viable embryo, the endometrium responds through species-specific transformation of the superficial tissue architecture, a process known as decidualization, allowing the organ to accommodate embryonic growth and placentation. The decidua will function like a barrier, protecting the embryo against the maternal immune system [see review 94].

Steroid hormones

The progesterone receptor (PR) was identified as one of the molecules that genetic polymorphisms were associated with the risk of implantation failure. The PR is encoded by PGR gene, and has two isoforms, PRA and PRB, both of them are expressed in the uterus [94]. Studies in mice showed that a deletion on PRA provokes severe abnormalities in ovarian and uterine function and impairs implantation [94]. A study in rabbits reported that favorable allele of PRG had an additive effect of 0.25 for implanted embryos and kits for litter size [95].

Estrogen receptor (ER) was also implied in uterine receptivity for embryo implantation. ER presents two isoforms, known as ERα (encoded by ESR1 gene) and ERβ (encoded by ESR2 gene). In mice, knocking out the ERα gene leads to unsuccessful implantation [94]. In pigs, favorable allele of ESR shows an additive effect between 0.45 and 0.75 piglets for litter size [96, 97]. In another hand, it has been shown that the ERBB receptor feedback inhibitor 1 (ERRFI1) gene is involved with successful implantation, which was associated with its suppression of ESR1 activity in the uterine epithelium, a crucial event for embryo implantation. Despite that the ovaries of ERRFI1 knockout female mice show a normal morphology and steroidogenesis function, its uterine horns do not develop an implantation site [98]. The steroid receptor coactivators (SRC1 and SRC2) present distinct physiological functions in the female reproductive system. For example, female mice lacking either SCR1 or SCR2 show progesterone resistance and compromised decidualization, whereas deletion of both SCR1 and SCR2 genes provoke infertility in female due to a complete blockage of decidualization [99], suggesting that one of the steroid receptor coactivators may, at least in part, compensate the absence of the other. Also the blockage of the repressor of estrogen receptor activity (REA), a significant modulator of estrogen responsiveness, was reported to induce implantation failures [100].

Moreover, prostaglandins (PGs) play an important role in various reproductive processes, including ovulation and implantation [101]. Cyclo-oxygenases (COX-1 and COX-2) are crucial enzymes in the synthesis of various PGs. Females lacking COX-1 and COX-2 are infertile, due to abnormalities in ovulation, fertilization, implantation, and decidualization [102]. A study in pigs showed that favorable allele of COX-2 had an additive effect of 0.3 piglets for litter size [103].

Cytokines

During the embryo implantation, the endometrium undergoes a dramatic transformation into a specialized transitory tissue known as the decidua in species with invasive hemochorial placenta, such as rodents and lagomorphs. In other species with no invasive placenta as pigs, the changes in endometrium ought to allow the trophoblast and its supporting layer of extraembryonic mesoderm to contact successfully with the uterine epithelium. The placenta surrounding the developing embryo facilitates the nutrient transfer and limits trophoblast invasion. The endometrium is recognized as an important site of production of cytokines and their receptors, which are also potential regulators of the phenotype and activation status of the uterine-resident leukocytes. Leukocytes infiltrated in the endometrium are required for the immunotolerance pathways that allow the maternal organism to accommodate the conceptus during implantation and placental development. Several cytokines, such as the macrophage colony-stimulating factor 1 (CSF1, also known as M-CSF), granulocyte colony-stimulating factor (CSF3, also known as G-CSF), and granulocyte-macrophage colony-stimulating factor (CSF2, also known as GM-CSF), are implicated in the recruitment and phenotypic regulation of the abundant populations of endometrial macrophages, granulocytes, and dendritic cells. These cytokines appear to be related to the successful embryo implantation and placental growth [104]. Also leukemia inhibitory factor (LIF), interleukin-6 (IL-6) and interleukin-11 (IL-11), and its receptor (IL-11Ra) have unquestionable roles in the implantation process [105-107]. Studies in pig have reported an association between certain polymorphisms in LIF gene with the number of piglets [108-111].

Growth factors

The epidermal growth factor (EGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), the vascular endothelial growth factors (VEGFs), the IGF-I and IGF-II as well as the IGF-binding protein-1 (IGFBP-1) are important factors for implantation. It was shown that EGF plays a critical role in trophoblast invasion, differentiation, and proliferation. EGF deficiency during pregnancy causes intrauterine growth retardation or abortion [112], while the deletion of epidermal growth factor receptor (EGFR or ERB1) gene causes failure in the embryo development and the placenta formation [113]. Likewise, other factors involved in the implantation process, such as HB-EGF, are expressed in endometrial stromal and epithelial cells. It has been demonstrated that HB-EGF regulates endometrial cell proliferation, glandular epithelial secretion, and decidual transformation [113]. Gene knockout studies reveal that deletion of HBEGF reduces litter size [114].

VEGF is an endothelial-cell specific mitogen in vitro, and it is the main factor responsible for de novo blood vessel formation (vasculogenesis) and angiogenesis in vivo [115]. Proper level of VEGF expression is required for implantation [116]. Many critical cell responses, including mitogenesis, proliferation, growth, differentiation, and angiogenesis, are mediated by IGF-I and IGF-II [117]. Both IGF-I and IGF-II are necessary to maintain normal embryonic growth rates [117]. In addition, higher expression of IGF1 mRNA has been observed during the peri-implantation period in mouse uterus [118]. Also in rabbit, it has been observed that IGF-II receptor plays an important role in embryo development and its implantation [119].

Transcription factors

Homeobox genes are transcriptional regulators evolutionarily conserved that control embryonic morphogenesis and differentiation [120]. Homeobox A (HOXA10 and HOXA11) and H6 homeobox 3 (HMX3) genes are expressed in uterine stromal cells during the receptivity period, and upregulated upon decidualization in response to steroid hormone stimulus. Ablation of HOXA10, HOXA11, or HMX3 genes leads to implantation defects [121-123]. MSX1 (also known as HOX7.1) and MSX2 also belong to homeobox genes, and deletion of both genes results in female infertility due to altered uterine polarity and integrity of the surface epithelium [124]. The Kruppel-like transcription factors (KLFs) are implicated in diverse cellular processes, including proliferation, differentiation, and apoptosis. The Kruppel-like factor 5 (KLF5), one of these transcription factors, is essential for the establishment of uterine receptivity [125], and its depletion induces implantation failure [126]. KLF9 is another KLF that plays an important role in blastocyst attachment; its loss reduces female fertility due to defective implantation [127]. The transcription factor named heart and neural crest derivatives-expressed transcript 2 (HAND2) and its protein are present in endometrial stromal cells adjacent to the surface epithelium in the uterus prior to the onset of implantation [128], suggesting that they may play a key role in uterine receptivity in mice [129]. Forkhead box protein A2 (FOXA2) is only expressed in the glandular epithelium of the uterus, and FOXA2 deficiency affect the endometrial gland formation and decidualization [130]. Deletion of chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), which is mainly expressed in uterine stromal cells, originates implantation failure due to disrupted uterine receptivity associated with high estrogen activity [131].

Morphogen genes, lipid mediatiors, integrins, mucins, and others molecules

Proteins belonging to the transforming growth factor beta superfamily (TGF-β), Wingless (WNT), Hedgehog, and Notch have been identified as morphogens. Morphogens act directly on angiogenesis, cell growth, pattern formation, embryo development, metabolic regulation, cell migration, and tissue repair, while also presenting neurotropic effects. Five TGF-βs have been identified, of which TGF-β1, β2, β3 are abundant in mammals. However, only TFG-β1 appears to limit the number of implanted embryos [132]. Activins are also members of the TGF-β superfamily that participate in the regulation of several biological processes, including cell differentiation and proliferation, apoptosis, and the immune response [133]. Activin A plays an important role in the implantation of embryos in rabbits and mice, promoting decidualization and preventing the activation of T cells [134]. Among all bone morphogenetic proteins expressed in the uterus, only BMP2 shows intense expression in the stromal cells surrounding the implanted embryo under response to progesterone [135]. In vitro studies in undifferentiated stromal cells demonstrated that silencing the expression of BMP2 efficiently blocks the decidualization [136]. Deletion of NODAL gene was accompanied by severe malformation of the maternal decidua basalis during placentation and increasing fetal losses before birth [137]. Several components of WNTs signaling pathway are spatiotemporally regulated in the peri-implantation uterus and are crucial to implantation. The absence of WNT4, WNT5a, and WNT7a in the uterus induces defective embryo implantation and subsequent decidualization failure [138-140], while deletion of WNT7b gene provokes fetal losses during mid-gestation, due to failure of chorioallantoic fusion [141]. Indian hedgehog (IHH) is a member of the Hedgehog family. It has been reported that conditional deletion IHH protein in the uterus results in implantation failure [142]. Activation of smoothened (SOM), another member of the Hedgehog family, provokes hypertrophy in uterus along and consequently failure to decidual response [143]. The NOTCH1 is responsible for cell survival, cell-to-cell communication, differentiation, and all fundamental processes for successful decidualization [144].

The blastocyst has a significant number of cannabinoid receptors (CB1) that are activated by the anandamide (AEA) produced in the uterus. It has been found that the levels of AEA are lower in the receptive uterus and at implantation sites than in the non-receptive uterus or at inter-implantation sites. These findings suggest the need for low AEA levels to activate uterine receptivity [145].

The integrin family of cell adhesion molecules is a major class of receptors for the extracellular matrix. They have many functions in cellular processes including differentiation, apoptosis, and attachment [146]. Previous studies have demonstrated that integrins exhibit distinctive expression patterns in different phases of uterine receptivity. Both α4β1 and αvβ3 integrins are present in uterus at the time of implantation, and intrauterine inhibition of these two molecules results in defective implantation [147, 148].

Symbol gene Name Effects References
Morphogens
TFG-β1 Transforming growth factor
beta 1
Failures in immunotolerance during embryo implantation [132, 133]
INHBA Activin A Limiting decidualization, and no preventing activation of T cells [134]
BMP2 Bone morphogenetic protein 2 Block the decidual reaction [135, 136]
NODAL NODAL Abnormal decidua basalis at midgestation and aberrant placental development [137]
WNT4, WNT5A, WNT7A and WNT7B Wingless-related MMTV integration site 4, 5a, 7a, 7b. Implantation and decidualization failures [138-141]
IHH Indian hedgehog Implantation failure [142]
SMO Smoothened Uterine hypertrophy with the reduction in the number of uterine glands and impaired decidualization [143]
NOTCH1 Notch1 Failure in decidualization [144]
Lipid mediators
AEA Anandamide Uterine receptivity [145]
Integrins
ITGA4/ITGB1 α4β1 integrin Implantation and decidualization failures [146, 147]
ITGAV/ITGB3 αvβ3 integrin Implantation and decidualization failures [146, 148]
Mucins
MUC1 Mucin 1 Embryo attachment failure [149, 151]
OVGP1 or MUC9 Oviductal glycoprotein 1 Fertilization and implantation failures [152]
Other molecules
CTNNB1 β-catenin Defects in embryonic ectoderm cell layer [153-154]
CX43 or CJA1 Connexin 43 Comprised decidualization; neovascularization defects [155]

Table 2.

Genes considered as critical to implantation.

Mucins also participate in the decidualization process. For example, mucin (MUC1) has been identified as an effective barrier that prevents embryo attachment to the uterine epithelium. Uterine MUC1 expression declines to undetectable levels prior to blastocyst attachment, reinforcing the impression that loss of MUC1 contributes to the establishment of a receptive uterus [149-151]. Other oviductal glycoprotein, as OVGP1 or MUC9, seems to affect the differentiation of endometrial and fetal cells by paracrine pathway, inhibiting the implantation and fetal development [152]. The active beta-catenin (CTNNB1) is only detected in morula and early blastocyst stages, its signal disappearing as soon as the blastocyst hatches from the zona pellucida [153]. Furthermore, deletion of CTNNB1 gene provokes severe gastrulation defects that results in embryonic lethality [154]. Connexin 43 (CX43, also known as GJA1) is a major gap junction protein that is markedly expressed in the uterine stromal cells surrounding the implanted embryo during early pregnancy. Deletion of CX43 gene leads to aberrant differentiation of uterine stromal cells, preventing the secretion of angiogenic factors, such as the VEGF. As consequence, the development of new blood vessels within the uterine stromal compartment suffers a striking impairment, resulting in the arrest of embryo growth and early pregnancy loss [155]. All these critical genes on successful implantation are listed on Table 2.

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5. Approaches for identifying genes in pigs and rabbits

In pigs and rabbits, genetic markers associated with reproductive traits have been identified through two complementary approaches. The first approach has been performed through unbiased genome scans with anonymous DNA markers, such as microsatellites and more recently with thousands of single nucleotide polymorphisms (SNPs), which have been used to identify quantitative trait loci (QTL) with effects on reproductive traits. Genome-wide scanning usually proceeds without any presuppositions regarding the importance of specific functional features of the investigated traits. Until now, a total of 28 suggestive QTL have been reported on pig chromosomes (SSC) 2, 6, 7, 8, 11, 12, 14, 15, 16, 17, and 18 for litter size [156-165], on SSC 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, and 18 for ovulation rate [165-171], and on SSC8 for the uterine capacity and prenatal loss [159, 166, 168].

In the second approach, the physiological role of candidate gene is known, and the gene is scanned for polymorphisms and associations to variations within the trait. Numerous genes have been evaluated as candidate genes affecting litter size in pigs, such as the estrogen receptor (ESR) [95-97], retinol binding protein 4 (RBP4) [172], gonadotrophin-releasing hormone receptor (GNRHR) [173], osteopontin (OPN) [174], folate-binding protein (FBP) [175], mitogen-activated protein kinase 3 (MAP3K3) [176], vascular endothelial growth factor receptor (KDR) [176], ERBB2 interacting protein (ERBB2IP) [176], and peroxisome proliferator-activated receptor delta (PPARD) [176]. Another candidate genes have been found for progesterone receptor (PRG), TIMP1, oviductal glycoprotein 1 (OVPG1), hydroxysteroid-17-beta- dehydrogenase 4 (HSD17B4), endoplasmic oxidoreductin-1-like protein (ERO1L), and octamer-binding transcription factor 4 (OCT4) in rabbits [177-181]. However, associations of these genes with litter size are always population specific, and the causative mutations underlying litter size remain unexplored.

DNA microarray is a new powerful tool for studying the molecular basis of interactions on a scale that is impossible using conventional analysis, making possible to examine the expression of thousands of genes simultaneously. In order to expand the understanding of the biological processes involved in the success of female reproduction, several studies in gene expression were developed in pigs targeting to identify the changes in ovaries [182, 183] and the endometrium at implantation [184-191]. For example, after selecting for 11 generations using an index of ovulation rate and embryonic survival, followed by 7 generations of selection for litter size, a total of 71 differentially expressed genes were identified in ovarian tissues of the selected and control lines at days 2–6 of the follicular stage of the estrous cycle [182]. Many of these genes had not been previously associated with reproduction. From these genes, 59 were homologous to genes of known function, 5 had no known matches in GenBank, and 7 were homologous to sequences of unknown function. Among the differentially expressed genes identified were those associated with the transport of cholesterol in ovarian follicles and the synthesis of steroids, such as collagen type I receptor (CD36L1, also known as scavenger receptor class B type I). The experiment also showed the importance of studying the expression of all these genes at different times of estrous cycle. For instance, genes of steroidogenic acute regulatory protein (STAR), 3-β-hydroxysteroid dehydrogenase (3βHSD), were overexpressed in higher producing pig ovaries at day 2 of analysis, while were underexpressed at day 3. In contrast, plasminogen activator inhibitor 1 (PAI1) and cytochrome P450 17-α-hydroxylase (CYP17) were overexpressed at day 3.

In a different study, 189 genes were found to be differentially expressed in the ovaries of pregnant pigs with high and low prolificacy, of which 72 were overexpressed in the high prolificacy group, while 133 of them were overexpressed in the low prolificacy group [183]. These genes appear to cluster in three main biological processes: the first group would be related to the immune system response activation against external stimulus, the second group included integrated genes that regulate maternal homeostasis by complement and coagulation cascades, and the third was involved in lipid and fatty acid enzymes of metabolic processes of the steroidogenesis pathway. Among validated genes, 2-5-oligoadenylate synthetase 1 (OAS1) was found overexpressed in high prolificacy females, while a family with sequence similarity with 46 member C (FAM46C), secreted phosphoprotein 1 (SPP1), thiosulfate sulfurtransferase (TST), and vitronectin (VTN), were reported overexpressed in low prolificacy females.

Recent microarray analysis revealed more than 2000 differentially expressed genes in endometrium between pregnant and cyclic pigs at the time of implantation, i.e., on days 12 [186], 13 [191], 14 [187], 15 [188], 16 [192], 18 [191], or 24 [191] of gestation. Most genes were involved in cell motility as well as apoptosis, transporter activity, calcium ion binding, lipid metabolic processes, hormone activity, vascular development and proteolysis, immune response. The identified and validated genes that are upregulated included ADAM metallopeptidase with thrombospondin type 1 motif 20 (ADAMTS20), mucin 4 (MUC4), leukemia inhibitory factor receptor alpha (LIFR), interleukin 6 receptor (IL6R), interferon regulatory factor 1 (IRF1), immunoresponsive 1 homolog (IRG1), secreted phosphoprotein 1 (SPP1), osterocrin (OSTN), nuclear receptor interacting protein 1 (NRIP1), proteolipid protein 1 (PLP1), signal transducer and activator of transcription 1 (STAT1), serpin peptidase inhibitor, clade B (ovalbumin), member 7 (SERPINB7), s100 calcium binding protein A 9 (S100A9), Erb-B2 receptor tyrosine kinase 3 (ERBB3), and fibroblast growth factor 9 (FGF9). Contrasting, mucin 5AC, oligomeric mucus/gel-forming (MUC5AC), interleukin 11 receptor alpha (IL11RA), interleukin 24 (IL24), brain and acute leukemia cytoplasmic (BAALC), defensin beta 1 (PBD-2), defensin beta 1 (PBD-2), cadherin 17 li (CDH17), FXYD domain containing ion transport regulator 4 (FXYD4), G protein-coupled receptor 83 (CPR83), and fibroblast growth factor receptor 3 (FGFR3) are downregulated [182-187, 191]. Litter size is controlled by a large number of genes.

Improvement in litter size has become one main objective of selection in pig and rabbit breeding programs. However, litter size is a complex trait, because it is controlled by numerous genes in complicated physiological networks such as those affecting ovulation rate, embryo survival, and uterine capacity. The genomic approaches, both QTL mapping and candidate gene analysis, have helped increase understanding in genetic control of litter size. Moreover newly developed tools based on DNA microarray techniques appear to be useful for in-depth understanding of the genetics of litter size in pigs and rabbits. A better understanding of genetic mechanisms controlling litter size could help to design more efficient selection strategies in improvement of this trait.

References

  1. 1. Peiró R, Gallego M, Blasco A, Santacreu MA. The effect of unilateral ovariectomy on early embryonic survival and embryo development in rabbits. World Rabbit Science. 2014; 22: 123–127.
  2. 2. Geisert RD, Schmitt RAM. Early embryonic survival in the pig: Can it be improved? Journal of Animal Science. 2002; 80: E54–E65.
  3. 3. Wilmut I, Sales DI, Ashworth CJ. Maternal and embryonic factors associated with prenatal loss in mammals. Journal of Reproduction and Fertility. 1986; 76: 851–864.
  4. 4. Argente MJ, Santacreu MA, Climent A, Blasco A. Effects of intrauterine crowding on available uterine space per fetus in rabbits. Livestock Science. 2008; 114: 211–219.
  5. 5. Ford SP. Embryonic and fetal development in different genotypes in pigs. Journal of Reproduction and Fertility. Supplement. 1997; 52: 165–176.
  6. 6. Christenson RK, Leymaster KA, Young LD. Justification of unilateral hysterectomy–ovariectomy as a model to evaluate uterine capacity in swine. Journal of Animal Science. 1987; 67: 738–744.
  7. 7. Blasco A, Bidanel JP, Bolet G, Haley CS, Santacreu MA. The genetics of prenatal survival of pigs and rabbits: a review. Livestock Production Science. 1993; 37: 1–21.
  8. 8. Santacreu MA, Mocé ML, Climent A, Blasco A. Divergent selection for uterine capacity in rabbits. II. Correlated response in litter size and its components estimated with a cryopreserved control population. Journal of Animal Science. 2005; 83: 2303–2307.
  9. 9. Ford SP, Vonnahme KA, Wilson ME. Uterine capacity in the pig reflects a combination of uterine environment and conceptus genotype effects. Journal of Animal Science. 2002; 80 (E. Suppl. 1); E66–E73.
  10. 10. Holt M, Vangen O, Farstad W. Components of litter size in mice after 110 generations of selection. Reproduction. 2004; 127: 587–592.
  11. 11. Pope WF, Xie S, Broerman DM, Nephew KP. Causes and consequences of early embryonic diversity in pigs. Journal of Reproduction and Fertility. Supplement. 1990; 40: 251–260.
  12. 12. Bazer FW, Thatcher WW, Martinant-Botte F, Terqui M, Lacroix MC, Bernard S, Revault M, Dubois DH. Composition of uterine flushings from Large White and prolific Chinese Meishan gilts. Reproduction Fertility and Development. 1991; 3: 51–60.
  13. 13. Bhatt P, Kadam K, Saxena A, Natraj U. Fertilization, embryonic development and oviductal environment: Role of estrogen induced oviductal glycoprotein. Indian Journal of Experimental Biology. 2004; 42: 1043–1055.
  14. 14. Herrler A, Krusche AC, Beier HM. Insulin and insuline-like growth factor-I promote rabbit blastocyst development and prevent apoptosis. Biology of Reproduction. 1998; 59: 1302–1310.
  15. 15. Buhi WC. Characterization and biological roles of oviduct-specific, oestrogen-dependent glycoprotein. Reproduction. 2002; 123: 355–362.
  16. 16. Buhi WC, Alvarez IM, Pickard AR, McIntush EW, Kouba AJ, Ashworth CJ, Smith MF. Expression of tissue inhibitor of metalloproteinase-1 protein and messenger ribonucleic acid by the oviduct of cyclic, early-pregnant, and ovariectomized steroid-treated gilts. Biology of Reproduction. 1997; 57: 7–15.
  17. 17. Kouba AJ, Alvarez IM, Buhi WC. Identification and localization of plasminogen activator inhibitor-1 within the porcine oviduct. Biology of Reproduction. 2000; 62: 501–510.
  18. 18. Riffo M, Gonzalez KD, Nieto A. Uteroglobin induces the development and cellular proliferation of the mouse early embryo. Journal of Experimental Zoology Part A: Ecological Genetics and Physiology. 2007; 307: 28–34.
  19. 19. Zerani M, Boiti C, Dall’Aglio C, Pascucci L, Maranesi M, Brecchia G. Leptin receptor expression and in vitro leptin actions on prostaglandin release and nitric oxide synthase activity in the rabbit oviduct. Journal of Endocrinology. 2005; 185: 319–325.
  20. 20. Wilde MH, Xie S, Day ML, Pope WF. Survival of small and large littermate blastocysts in swine after synchronous and asynchronous transfer procedures. Theriogenology. 1988; 30: 1069–1074.
  21. 21. Xie S, Broermann DM, Nephew KP, Bishop MD, Pope WF. Relationship between oocyte maturation and fertilization on zygotic diversity in swine. Journal of Animal Science. 1990; 68: 2027–2033.
  22. 22. Adams CE. Studies on prenatal mortality in rabbit, Oryctolagus cuniculus: The amount and distribution of loss before and after implantation. Journal of Endocrinology. 1960; 19: 325–344.
  23. 23. Hafez ESE, Tsutsumi Y. Changes in endometrial vascularity during implantation and pregnancy in the rabbit. American Journal Anatomy. 1966; 118: 249–282.
  24. 24. Argente MJ, Santacreu MA, Climent A, Blasco A. Relationships between uterine and fetal traits in rabbits selected on uterine capacity. Journal of Animal Science. 2003; 81: 1265–1273.
  25. 25. Mocé ML, Santacreu MA, Climent A, Blasco A. The effect of divergent selection for uterine capacity on prenatal survival in rabbits: maternal and embryonic genetic effects. Journal of Animal Science. 2004; 82: 68–73.
  26. 26. Argente MJ, Santacreu MA, Climent A, Blasco A. Influence of available uterine space per fetus on fetal development and prenatal survival in rabbits selected for uterine capacity. Livestock Science. 2006; 102: 83–91.
  27. 27. Chen ZY, Dziuk, PJ. Influence of initial length of uterus per embryo and gestation stage on prenatal survival, development, and sex ratio. Journal of Animal Science. 1993; 71: 1895–1901.
  28. 28. Wilson ME, Biensen NJ, Ford SP. Novel insight into the control of litter size in the pig, using placental efficiency as a selection tool. Journal of Animal Science.1999; 77: 1654–1658.
  29. 29. Foxcroft GR, Dixon WT, Dyck MK, Novak S, Harding JC, Almeida FC. Prenatal programming of postnatal development in the pig. Society for Reproduction and Fertility Supplement. 2009; 66: 213–231.
  30. 30. Blasco A, Bidanel JP, Haley C. Genetics and neonatal survival. In: Varley MA, editors. The Neonatal Pig. Development and Survival. CAB International: Wallingford, Oxon, UK; 1995. 17–38 pp.
  31. 31. Rochambeau H De, Duzert R, Tudela F. Long term selection experiments in rabbit. Estimation of genetic progress on litter size at weaning. Proceedings of 6th World Congress on Genetics Applied to Livestock Production. 1998; 26: 112–115.
  32. 32. García ML, Baselga M. Estimation of genetic response to selection in litter size of rabbits using a cryopreserved control population. Livestock Production Science. 2002; 74: 45–53.
  33. 33. Haley CS, Avalos E, Smith C. Selection for litter size in the pig. Animal Breeding Abstract. 1988; 56: 319–332.
  34. 34. Bolet B, Bidanel JP, Olliver L. Selection for litter size in pigs. II. Efficiency of closed and open selection lines. Genetic Selection and Evolution. 2001; 33: 515–528.
  35. 35. Estany J, Villalba D, Tibau J, Soler J, Babot D, Noguera JL. Correlated response to selection for litter size in pigs: I. Growth, fat deposition, and feeding behavior traits. Journal of Animal Science. 2002; 80: 2556–2565.
  36. 36. Holl JW, Robinson OW. Result from nine generations of selection for increased litter size in swine. Journal of Animal Sicience. 2003; 81: 624–629.
  37. 37. Bradford GE. Genetic control of ovulation rate and embryo survival in mice. I. Response to selection. Genetics. 1969; 61: 905–921.
  38. 38. Falconer DS. Improvement of litter size in a strain of mice at a selection limit. Genetics Research. 1971; 17: 215–235.
  39. 39. Bakker H, Wallinga JH, Politiek RD. Reproduction and body weight of mice after long term selection for large litter size. Journal of Animal Science. 1978; 46: 1572–1580.
  40. 40. Gion JM, Clutter AC, Nielsen MK. Alternative methods of selection for litter size in mice: II. Response to thirteen generations of selection. Journal of Animal Science.1990; 68: 3543–3556.
  41. 41. Nielsen B, Su G, Lund MS, Madsen P. Selection for increased number of piglets at d 5 after farrowing has increased litter size and reduced piglet mortality. Journal of Animal Science. 2014; 91(6): 2575–2582.
  42. 42. Laborda P, Mocé ML, Santacreu MA, Blasco A. Selection for ovulation rate in rabbits: Genetic parameters, direct response, and correlated response on litter size. Journal of Animal Science. 2011; 89: 2981–2987.
  43. 43. Cunningham PJ, England ME, Young LD, Zimmerman DR. Selection for ovulation rate in swine: Correlated response in litter size and weight. Journal of Animal Science. 1979; 48: 509–516.
  44. 44. Leymaster KA, Christenson RK. Direct and correlated responses to selection for ovulation rate or uterine capacity in swine. Journal of Animal Science, 2000; 78(Suppl 1): 68.
  45. 45. Rosendo AT, Druet T, Gogué J, Bidanel JP. Direct responses to six generations of selection for ovulation rate or prenatal survival in Large White pigs. Journal of Animal Science. 2007; 85: 356–364.
  46. 46. Land RD, Falconer DS. Genetic studies of ovulation rate in the mouse. Genetics Research.1969; 13: 25–46.
  47. 47. Blasco A, Argente MJ, Haley CS, Santacreu MA. Relationships between components of litter size in unilaterally ovariectomized and intact rabbit does. Journal of Animal Science. 1994; 72: 3066–3072.
  48. 48. Clutter AC, Nielsen MK, Johnson RK. Alternative methods of selection for litter size in mice: I. Characterization of base population and development of methods. Journal of Animal Science. 1990; 68: 3536–3542.
  49. 49. Bolet G, Santacreu MA, Argente MJ, Climent A, Blasco A. Divergent selection for uterine capacity in unilaterally ovariectomized rabbits. I. Phenotypic and genetic parameters. Proceedings of 5th World Congress Genetic Applied Livestock Production. 1994; 19: 261–264.
  50. 50. Clutter AC, Kochera Kirby YL, Nielsen MK. Uterine capacity and ovulation rate in mice selected 21 generations on alternative criteria to increase litter size. Journal of Animal Science. 1994; 72: 577–583.
  51. 51. Mesa H, Safranski TJ, Fischer KA, Cammack KM, Lamberson WR. Selection for placental efficiency in swine: Genetic parameters and trends. Journal of Animal Science. 2005; 83: 983–991.
  52. 52. Mesa H, Cammack KM, Safranski TJ, Green JA,Lamberson WR. Selection for placental efficiency in swine: conceptus development. Journal of Animal Science. 2012; 90: 4217–4222.
  53. 53. Johnson RK, Zimmerman DR; Kittok RK. Selection for components of reproduction in swine. Livestock Production Science. 1984; 11: 541–558.
  54. 54. Bennett GL, Leymaster KA. Integration of ovulation rate, potential embryonic viability and uterine capacity into a model of litter size in swine. Journal of Animal Science. 1989; 67: 1230–1241.
  55. 55. Johnson RK, Nielsen MK, Casey DS. Responses in ovulation rate, embryonal survival and litter traits in swine to 14 generations of selection to increase litter size. Journal of Animal Science. 1999; 77: 541–557.
  56. 56. Kirby YK, Nielsen MK, Alternative methods of selection for litter size in mice: III. Response to 21 generations of selection. Journal of Animal Science. 1993; 71: 571–578.
  57. 57. Falconer DS, Mackay TFC. Introduction to Quantitative Genetics, 4th edn Harlow, UK: Addison Wesley Longman. 1996. 317–339 pp.
  58. 58. Ziadi C, Mocé ML, Laborda P, Blasco A, Santacreu MA. Genetic selection for ovulation rate and litter size in rabbits: Estimation of genetic parameters and direct and correlated responses. Journal of Animal Science. 2013; 91: 3113–3120.
  59. 59. Ruiz-Flores A, Johnson RK. Direct and correlated responses to two-stage selection for ovulation rate and number of fully formed pigs at birth in swine. Journal of Animal Science. 2001; 79: 2286–2299.
  60. 60. Hill WG, Mulder HA. Genetic analysis of environmental variation. Genetics Research. 2010; 92: 381–395.
  61. 61. Argente MJ, García ML, Muelas R, Blasco A. Effect of selection for residual variance of litter size on components of litter size in rabbits. Proceedings of 10th World Congress on Genetics Applied to Livestock Production. 2014; 149: 244–250.
  62. 62. Schultz RM. The molecular foundations of the maternal to zygotic transition in the preimplantation embryo. Human Reproduction Update. 2002; 8: 323–331.
  63. 63. Latham KE, Kutyna K, Wang Q. Genetic variation in trophectoderm function in parthenogenetic mouse embryos. Developmental Genetics. 1999; 24: 329–335.
  64. 64. Schultz RM. Regulation of zygotic gene activation in the mouse. BioEssays. 1993; 8: 531–538.
  65. 65. Jarrell VL, Day BN, Praher RS. The transition from maternal to zygotic control of development occurs during the 4-cell stage in the domestic pig, Sus scrofa: Quantitative and qualitative aspects of protein synthesis. Biology of Reproduction. 1991; 44: 62–68.
  66. 66. Telford NA, Hogan A, Franz CR, Schultz GA. Expression of genes for insulin and insulin-like growth factors and receptors in early postimplantation mouse embryos and embryonal carcinoma cells. Molecular Reproduction and Development. 1990; 27: 81–92.
  67. 67. Murchison EP, Stein P, Xuan Z, Pan H, Zhang MQ, Schultz RM, Hannon GJ. Critical roles for Dicer in the female germline. Genes & Development. 2007; 21: 682–693.
  68. 68. Stowe HM, Curry E, Calcatera SM, Krisher RL, Paczkowski M, Pratt SL. Cloning and expression of porcine Dicer and the impact of developmental stage and culture conditions on MicroRNA expression in porcine embryos. Gene. 2012; 501(2): 198–205.
  69. 69. Le Masson F, Razak Z, Kaigo M, Audouard C, Charry C, Cooke H, Westwood JT, Christians ES. Identification of heat shock factor 1 molecular and cellular targets during embryonic and adult female meiosis. Molecular and Cellular Biology. 2011; 31(16): 3410–3423.
  70. 70. Kohata C, Izquierdo-Rico MJ, Romar R, Funahashi H. Development competence and relative transcript abundance of oocytes derived from small and medium follicles of prepubertal gilts. Theriogenology. 2013; 80(9): 970–978.
  71. 71. Mtango NR, Sutovsky M, Susor A, Zhong Z, Latham KE, Sutovsky P. Essential role of maternal UCHL1 and UCHL3 in fertilization and preimplantation embryo development. Journal of Cellular Physiology. 2012; 227(4): 1592–1603.
  72. 72. Yi YJ, Manandhar G, Sutovsky M, Li R, Jonáková V, Oko R, Park CS, Prather RS, Sutovsky P. Ubiquitin C-terminal hydrolase-activity is involved in sperm acrosomal function and anti-polyspermy defense during porcine fertilization. Biology of Reproduction. 2007; 77(5): 780–793.
  73. 73. Lykke-Andersen K, Gilchrist MJ, Grabarek JB, Das P, Miska E, Zernicka-Goetz M. Maternal Argonaute 2 is essential for early mouse development at the maternal-zygotic transition. Molecular Biology of the Cell. 2008; 19(10): 4383–4392.
  74. 74. Krawczynski K, Najmula J, Bauersachs S, Kaczmarek MM. MicroRNAome of porcine conceptuses and trophoblasts: expression profile of micromas and their potential to regulate genes crucial for establishment of pregnancy. Biology of Reproduction. 2015; 92(1): 21.
  75. 75. Tong ZB, Gold L, Pfeifer KE, Dorward H, Lee E, Bondy CA, Dean J, Nelson LM. Mater, a maternal effect gene required for early embryonic development in mice. Nature Genetics. 2000; 26(3): 267–268.
  76. 76. Pisani LF, Ramelli P, Lazzari B, Braglia S, Ceciliani F, Mariani P. Characterization of maternal antigen that embryos require (MATER/NLRP5) gene and protein in pig somatic tissues and germ cells. Journal of Reproduction and Development. 2010; 56(1): 41–48.
  77. 77. Wu X, Viveiros MM, Eppig JJ, Bai Y, Fitzpatrick SL, Matzuk MM. Zygote arrest 1 (Zar1) is a novel maternal-effect gene critical for the oocyte-to-embryo transition. Nature Genetics. 2003; 33: 187–191.
  78. 78. Uzbekova S, Roy-Sabau M, Dalbiès-Tran R, Perreau C, Papillier P, Mompart F, Thelie A, Pennetier S, Cognie J, Cadoret V, Royere D, Monget P, Mermillod P. Zygote arrest 1 gene in pig, cattle and human: Evidence of different transcript variants in male and female germ cells. Reproductive Biology and Endocrinology. 2006; 4: 12.
  79. 79. Esposito G, Vitale AM, Leijten FP, Strik AM, Koonen-Reemst AM, Yurttas P, Robben TJ, Coonrod S, Gossen JA. Peptidylarginine deiminase (PAD) 6 is essential for oocyte cytoskeletal sheet formation and female fertility. Molecular and Cellular Endocrinology. 2007; 273: 25–31.
  80. 80. Xia X, Yan C, Wu W, Zhou Y, Hou L, Zuo B, Xu D, Ren Z, Xiong Y. Characterization of the porcine peptidylarginine deiminase type VI gene (PADI6) promoter: Sp1 regulates basal transcription of the porcine PADI6. Gene. 2015; 1119(15): 1151.
  81. 81. Cinquanta M, Rovescalli AC, Kozak CA, Nirenberg M. Mouse Sebox homeobox gene expression in skin, brain, oocytes, and two-cell embryos. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97: 8904–8909.
  82. 82. Zheng Z, Zhao MH, Jia JL, Heo YT, Cui XS, Oh JS, Kim NH. Knockdown of maternal homeobox transcription factor SEBOX gene impaired early embryonic development in porcine parthenotes. Journal of Reproduction and Development. 2013; 59(6): 557–562.
  83. 83. Bultman SJ, Gebuhr TC, Pan H, Svoboda P, Schultz RM, Magnuson T. Maternal BRG1 regulates zygotic genome activation in the mouse. Genes and Development. 2006; 20: 1744–1754.
  84. 84. Magnani L, Cabot RA. Manipulation of SMARCA2 and SMARCA4 transcript levels in porcine embryos differentially alters development and expression of SMARCA1, SOX2, NANOG, and EIF1. Reproduction. 2009; 137(1): 23–33.
  85. 85. Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM, Chaillet JR. Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell. 2001; 104(6): 829–838.
  86. 86. Huan Y, Wang H, Wu Z, Zhang J, Liu Z, He H. The expression patterns of DNA methylation reprogramming related genes are associated with the developmental competence of cloned embryos after zygotic genome activation in pigs. Gene Expression Patterns. 2015; 18(1–2): 1–7.
  87. 87. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99(3): 247–257.
  88. 88. Lee K, Hamm J, Whitworth K, Spate L, Park KW, Murphy CN, Prather RS. Dynamics of TET family expression in porcine preimplantation embryos is related to zygotic genome activation and required for the maintenance of NANOG. Development Biology. 2014: 386(1): 86–95.
  89. 89. Henderson GRW, Brahmasani SR, Yelisetti UM, Konijeti S, Katari VC, Sisinthy S. Candidate gene expression patterns in rabbit preimplantation embryos developed in vivo and in vitro. Journal of Assisted Reproduction and Genetics. 2014; 31(7): 899–911.
  90. 90. Táncos Z, Bock I, Nemes C, Kobolák J, Dinnyés A. Cloning and characterization of rabbit POU5F1, SOX2, KLF4, C-MYC and NANOG pluripotency-associated genes. Gene. 2015; 566(2): 148–157.
  91. 91. Yamaguchi S, Kurimoto K, Yabuta Y, Sasaki H, Nakatsuji N, Saitou M, Tada T. Conditional knockdown of Nanog induces apoptotic cell death in mouse migrating primordial germ cells. Development. 2009; 136: 4011–4020.
  92. 92. Kehler J, Tolkunova E, Koschorz B, Pesce M, Gentile L, Boiani M, Lomeli H, Nagy A, McLaughlin KJ, Sholer HR, Tomilin A. Oct4 is required for primordial germ cell survival. EMBO Report. 2004; 5: 1078–1083.
  93. 93. du Puy L, Lopes SM, Haagsman HP, Roelen BA. Analysis of co-expression of OCT4, NANOG and SOX2 in pluripotent cells of the porcine embryo, in vivo and in vitro. Theriogenology. 2011; 75(3): 513–526.
  94. 94. Zhang S, Lin H, Kong S, Wang S, Wang H, Wang H, Armant DR. Physiological and molecular determinants of embryo implantation. Molecular Aspects of Medicine. 2013; 34(5): 939–980.
  95. 95. Peiró R, Merchán M, Santacreu MA, Argente MJ, García ML, Folch JM, Blasco A. Identification of single-nucleotide polymorphism in the progesterone receptor gene and its association with reproductive traits in rabbits. Genetics. 2008; 180(3): 1699–1705.
  96. 96. Short TH, Rothschild MF, Southwood OI, McLaren DG, de Vries A, van der Steen H, Eckardt GR, Tuggle CK, Helm J, Vaske DA, Mileham AJ, Plastow GS. Effect of the estrogen receptor locus on reproduction and production traits in four commercial pig lines. Journal of Animal Science. 1997; 75(12): 3138–3142.
  97. 97. Rothschild MF, Jacobson C, Vaske DA, Tuggle C, Wang L, Short T, Eckardt G, Sasaki S, Vicent, A, McLaren D, Southwood O, van der Steen, H, Mileham A, Plastow G. The estrogen receptor locus is associated with a major gene influencing litter size in pigs. Proceedings of the National Academy of Science of the United States of America. 1996; 93(1): 201–205.
  98. 98. Kim TH, Lee D-K, Franco HL, Lydon JP, Jeong JW. ERBB receptor feedback inhibitor 1 regulation of estrogen receptor activity is critical for uterine implantation in mice. Biology of Reproduction. 2010; 82(4): 706–713.
  99. 99. Xu J, Li Q. Review of the in vivo functions of the p160 steroid receptor coactivator family. Molecular Endocrinology. 2003; 17(9): 1681–1692.
  100. 100. [100] Park S, Yoon S, Zhao Y, Park SE, Liao L, Xu J, Lydon JP, DeMayo FJ, O'Malley BW, Bagchi MK, Katzenellenbogen BS. Uterine development and fertility are dependent on gene dosage of the nuclear receptor coregulator REA. Endocrinology. 2012; 153(8): 3982–3994.
  101. 101. Salleh N. Diverse roles of prostaglandins in blastocyst implantation. Scientific World Journal. 2014; 968141.
  102. 102. Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, Dey SK. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell. 1997; 91(2): 197–208.
  103. 103. Sironen AI, Uimari P, Serenius T, Mote B, Rothschild M, Vilkki J. Effect of polymorphisms in candidate genes on reproduction traits in Finnish pig populations. Journal of Animal Science. 2010; 88(3): 821-827.
  104. 104. Robertson AS, Allanson M, Mau VJ. Molecular regulation of uterine leukocyte recruitment during early pregnancy in the mouse. Placenta. 1998; 19(1): 101–119.
  105. 105. Kamei Y, Tsutsumi O, Kuwabara Y, Taketani Y. Intra-uterine growth retardation and fetal losses are caused by epidermal growth factor deficiency in mice. American Journal of Physiology. 1993; 264(3): R597–R600.
  106. 106. Robertson SA, O’Connell A, Ramsey A. The effect of interleukin-6 deficiency on implantation, fetal development and parturition in mice. Proceedings of the Australian Society for Reproductive biology. 2000; 31: 97.
  107. 107. Robb L, Li R, Hartley L, Nandurkar H, Koentgen F, Begley CG. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nature Medicine. 1998; 4(3): 303–308.
  108. 108. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo SJ. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992; 359(6390): 76-79.
  109. 109. Mucha A, Ropka-Molik K, Piórkowska K, Tyra M, Oczkowicz M. Effect of EGF, AREG and LIF genes polymorphisms on reproductive traits in pigs. Animal Reproduction Science. 2013; 137(1-2): 88-92.
  110. 110. Lin HC, Liu GF, Wang AG, Kong LJ, Wang XF, Fu JL. Effect of polymorphism in the leukemia inhibitory factor gene on litter size in large white pigs. Molecular Biology Reports. 2009; 36(7): 1833-1838.
  111. 111. Spötter A, Müller S, Hamann H, Distl O. Effect of polymorphisms in the genes for LIF and RBP4 on litter size in two German pig lines. Reproduction in Domestic Animal. 2009; 44(1): 100-105.
  112. 112. Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, Barnard JA, Yuspa SH, Coffey RJ, Magnusom T. Targeted disruption of mouse EGF receptor: Effect of genetic background on mutant phenotype. Science. 1995; 269(5221): 230–234.
  113. 113. Xie H, Wang H, Tranguch S, Iwamoto R, Mekada E, Demayo FJ, Lydon JP, Das SK, Dey SK. Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(46): 18315-18320.
  114. 114. Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress. Endocrine Reviews. 2004; 25(4): 581–611.
  115. 115. Halder JB, Zhao X, Soker S, Paria BC, Klagsbrun M, Das SK, Dey SK. Differential expression of VEGF isoforms and VEGF164-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF164 in vascular permeability and angiogenesis during implantation. Genesis. 2000; 26: 213–224.
  116. 116. Lammers R, Gray A, Schlessinger J, Ullrich A. Differential signalling potential of insulin- and IGF-1-receptor cytoplasmic domains. EMBO Journal. 1989; 8(5): 1369–1375.
  117. 117. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993; 75(1): 73–82.
  118. 118. Kapur S, Tamada H, Dey SK, Andrews GK. Expression of insulin-like growth factor-I (IGF-I) and its receptor in the peri-implantation mouse uterus, and cell-specific regulation of IGF-I gene expression by estradiol and progesterone. Biology of Reproduction. 1992; 46(2): 208–219.
  119. 119. Llobat L, Marcos-Jiménez F, Peñaranda DS, Thieme R, Navarrete A, Vicente JS. mRNA expression in rabbit blastocyst and endometrial tissue of candidate gene involved in gestational losses. Reproduction in Domestic Animals. 2012.; 47: 281-287.
  120. 120. Krumlauf R. Hox genes in vertebrate development. Cell. 1994; 78(2): 191–201.
  121. 121. Gendron RL, Paradis H, Hsieh-Li HM, Lee DW, Potter SS, Markoff E. Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biology of Reproduction. 1997; 56(5): 1097–1105.
  122. 122. Bagot CN, Kliman HJ, Taylor HS. Maternal Hoxa10 is required for pinopod formation in the development of mouse uterine receptivity to embryo implantation. Developmental Dynamics. 2001; 222(3): 538–544.
  123. 123. Wang W, Van De Water T, Lufkin T. Inner ear and maternal reproductive defects in mice lacking the Hmx3 homeobox gene. Development. 1998; 125(4): 621–634.
  124. 124. Daikoku T, Cha J, Sun X, Tranguch S, Xie H, Fujita T, Hirota Y, Lydon J, DeMayo F, MaxsonR, Dey SK. Conditional deletion of MSX homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. Developmental Cell. 2011; 21(6):1014-1025.
  125. 125. Cha J, Sun X, Dey SK. Mechanisms of implantation: Strategies for successful pregnancy. Nature Medicine. 2012; 18: 1754-1767.
  126. 126. Sun X, Zhang L, Xie H, Wan H, Magella B, Whitsett JA, Dey SK. Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(4): 1145–1150.
  127. 127. Simmen RCM, Eason RR, McQuown JR, Linz AL, Kang TJ, Chatman L, Jr., Till SR, Fujii-Kuriyama Y, Simmen FA, Oh SP. Subfertility, uterine hypoplasia, and partial progesterone resistance in mice lacking the Kruppel-like factor 9/basic transcription element-binding protein-1 (Bteb1) gene. Journal of Biological Chemistry. 2004; 279(28): 29286–29294.
  128. 128. Huyen D, Bany B. Evidence for a conserved function of heart- and neural crest derivatives-expressed transcript 2 (Hand2) in mouse and human decidualization. Reproduction (Cambridge, England). 2011; 142(2): 353-368.
  129. 129. Li Q, Kannan A, DeMayo FJ, Lydon JP, Cooke PS, Yamagishi H, Srivastava D, Bagchi MK, Bagchi IC. The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science. 2011; 331(6019): 912–916.
  130. 130. Jeong JW, Kwak I, Lee KY, Kim TH, Large MJ, Stewart CL, Kaestner KH, Lydon JP, DeMayo FJ. Foxa2 is essential for mouse endometrial gland development and fertility. Biology of Reproduction. 2010; 83(3): 396-403.
  131. 131. Kurihara I, Lee D-K, Petit FG, Jeong J, Lee K, Lydon JP, Demayo FJ, Tsai MJ, Tsai SY. COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. Barsh G, ed. PLoS Genetics. 2007; 3(6): e102.
  132. 132. Roelen BAJ, Lin HY, Knežević V, Freund E, Mummery C. Expression of TGF-βs and their receptors during implantation and organogenesis of the mouse embryo. Developmental Biology. 2002; 166(2): 716-728.
  133. 133. Jones RL, Salamonsen LA, Findlay JK. Potential roles for endometrial inhibins, activins and follistatin during human embryo implantation and early pregnancy. Trends in Endocrinology and Metabolism. 2002; 13(4): 144–150.
  134. 134. Jones RL, Findlay JK, Farnworth PG, Robertson DM, Wallace E, Salamonsen LA. Activin A and inhibin A differentially regulate human uterine matrix metalloproteinases: Potential interactionsduring decidualization and trophoblast invasion. Endocrinology. 2006; 147(2): 724–732.
  135. 135. Paria BC, Ma W, Tan J, Raja S, Das SK, Dey SK, Hogan BL. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proceedings of the National Academy of Sciences of the United States of America. 2001; 98(3): 1047–1052.
  136. 136. Li Q, Kannan A, Wang W, Demayo FJ, Taylor RN, Bagchi MK, Bagchi IC. Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. Journal of Biological Chemistry. 2007; 282(43): 31725–31732.
  137. 137. Park CB, DeMayo FJ, Lydon JP, Dufort D. NODAL in the uterus is necessary for proper placental development and maintenance of pregnancy. Biology of Reproduction. 2012; 86(6):194.
  138. 138. Franco HL, Dai D, Lee KY, Rubel CA, Roop D, Boerboom D, Jeong JW, Lydon JP, Bagchi IC, Bagchi MK, DeMayo FJ. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. FASEB Journal. 2011; 25(4): 1176-1187.
  139. 139. Cha J, Bartos A, Park C, Sun X, Li Y, Cha SW, Ajima R, Ho HY, Yamaguchi TP, Dey SK. Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR signaling. Cell Reports. 2014; 8(2): 382-392.
  140. 140. Dunlap KA, Filant J, Hayashi K, Rucker EB 3rd, Song G, Deng JM, Behringer RR, DeMayo FJ, Lydon J, Jeong JW, Spencer TE. Postnatal deletion of Wnt7a inhibits uterine gland morphogenesis and compromises adult fertility in mice. Biology of Reproduction. 2011; 85(2): 386-396.
  141. 141. Parr BA, Cornish VA, Cybulsky MI, McMahon AP. Wnt7b regulates placental development in mice. Developmental Biology. 2001; 237(2): 324–332.
  142. 142. Lee K, Jeong J, Kwak I, Yu CT, Lanske B, Soegiarto DW, Toftgard R, Tsai MJ, Tsai S, Lydon JP, DeMayo FJ. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nature Genetics. 2006; 38(10):1204–1209.
  143. 143. Franco HL, Lee KY, Rubel CA, Creighton CJ, White LD, Broaddus RR, Lewis MT, Lydon JP, Jeong JW, DeMayo FJ. Constitutive activation of smoothened leads to female infertility and altered uterine differentiation in the mouse. Biology of Reproduction. 2010; 82(5): 991-999.
  144. 144. Afshar Y, Jeong JW, Roqueiro D, DeMayo F, Lydon J, Radtke F, Radnor R, Miele L, Fazleabas A. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB Journal. 2012; 26(1): 282-294.
  145. 145. Schmid PC, Paria BC, Krebsbach RJ, Schmid HHO, Dey SK. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proceedings of the National Academy of Sciences of the United States of America. 1997; 94(8): 4188-4192.
  146. 146. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nature Reviews Cancer. 2010; 10(1): 9-22.
  147. 147. Illera MJ, Lorenzo PL, Gui YT, Beyler SA, Apparao KB, Lessey BA. A role alphavbeta3 integrin during implantation in rabbit model. Biology of Reproduction. 2003; 68: 766-771.
  148. 148. Johnson GA, Robert C, Burghardt RC, Bazer FW. Osteopontin: A leading candidate adhesion molecule for implantation in pigs and sheep. Journal of Animal Science and Biotechnology. 2014; 5: 56-70.
  149. 149. Hoffman LH, Olson Ge, Carson DD, Chilton BS. Progesterone and implanting blastocysts regulate Muc1 expression in rabbit uterine epithelium. Endocrinology. 1998; 139: 266-271.
  150. 150. Ren Q, Guan S, Fu J, Wang A. Temporal and spatial expression of Muc1 during implantation in sows. International Journal of Molecular Sciences. 2010; 11: 2322-2335.
  151. 151. Surveyor GA, Gendler SJ, Pemberton L, Das SK, Chakraborty I, Julian J, Pimental RA, Wegner CC, Dey SK, Carson DD. Expression and steroid hormonal control of Muc-1 in the mouse uterus. Endocrinology. 1995; 136(8): 3639-3647.
  152. 152. Wang J, Huang ZP, Nie GY, Salamonsen LA, Shen QX. Immunoneutralization of endometrial monoclonal nonspecific suppressor factor beta (MNSFβ) inhibits mouse embryo implantation in vivo. Molecular Reproduction Development. 2007; 74(11): 1419–1427.
  153. 153. Jha RK, Titus S, Saxena D, Kumar PG, Laloraya M. Profiling of E-cadherin, beta-catenin and Ca(2+) in embryo-uterine interactions at implantation. FEBS Letters. 2006; 580: 5653-5660.
  154. 154. Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K, Kemler R. Lack of beta-catenin affects mouse development at gastrulation. Development. 1995 121: 3529-3537.
  155. 155. Laws MJ, Taylor RN, Sidell N, DeMayo FJ, Lydon JP, Gutstein DE, Bagchi MK, Bagchi IC. Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development. 2008; 135(15): 2659-2668.
  156. 156. Yasue H, Mikawa S, Uenishi H, Wada Y. Analysis of allele segregation distortion in a swine resource family. Animal Biotechnology. 1999; 10(3): 147–152.
  157. 157. Cassady JP, Johnson RK, Pomp D, Rohrer GA, Van Vleck LD, Spiegel EK, Gilson KM. Identification of quantitative trait loci affecting reproduction in pigs. Journal of Animal Science. 2001; 79(3): 623–633.
  158. 158. de Koning DJ, Rattink AP, Harlizius B, Groenen MAM, Brascamp EW, van Arendonk JAM. Detection and characterization of quantitative trait loci for growth and reproduction traits in pigs. Livestock Production Science. 2001; 72(3): 185–198.
  159. 159. King AH, Jiang Z, Gibson JP, Haley CS, Archibald AL. Mapping quantitative trait loci affecting female reproductive traitson porcine chromosome 8. Biology of Reproduction. 2003; 68(6): 2172–2199.
  160. 160. Holl JW, Cassady JP, Pomp D, Johnson RK. A genome scan for quantitative trait loci and imprinted regions affecting reproduction in pigs. Journal of Animal Science. 2004; 82(12): 3421–3429.
  161. 161. Tribout T, Iannuccelli N, Druet T, Gilbert H, Riquet J, Gueblez R, Mercat MJ, Bidanel JP, Milan D, Le RP. Detection of quantitative trait loci for reproduction and production traits in large white and French Landrace pig populations. Genetics Selection Evolution. 2008; 40(1): 61–78.
  162. 162. Li K, Ren J, Xing Y, Zhang Z, Ma J, Guo Y, Huang L. Quantitative trait loci for litter size and prenatal loss in a White DurocxChinese Erhualian resource population. Animal Genetics. 2009; 40(6): 963–966.
  163. 163. Onteru SK, Fan B, Nikkilä MT, Garrick DJ, Stalder KJ, Rothschild MF. Whole-genome association analyses for lifetime reproductive traits in the pig. Journal of Animal Science. 2011; 89(4): 988-995.
  164. 164. Onteru SK, Fan B, Du ZQ, Garrick DJ, Stalder KJ, Rothschild MF. A whole-genome association study for pig reproductive traits. Animal Genetics. 2012; 43(1): 18–26.
  165. 165. Hernandez SC, Finlayson HA, Ashworth CJ, Haley CS, Archibald AL. A genome-wide linkage analysis for reproductive traits in F2 large white × Meishan cross gilts. Animal Genetics. 2014; 45(2): 191-197.
  166. 166. Wilkie PJ, Paszek AA, Beattie CW, Alexander LJ, Wheeler MB, Schook LB. A genomic scan of porcine reproductive traits reveals possible quantitative trait loci (QTLs) for number of corpora lutea. Mammalian Genome. 1990; 10(6): 573–578.
  167. 167. Rathje TA, Rohrer GA, Johnson RK. Evidence for quantitative trait loci affecting ovulation rate in pigs. Journal of Animal Science. 1997; 75(6): 1486–1494.
  168. 168. Rohrer GA, Ford JJ, Wise TH, Vallet JL, Christenson RK. Identification of quantitative trait loci affecting female reproductive traits in a multigeneration Meishan-White composite swine population. Journal of Animal Science. 1999; 77(6): 1385–1391.
  169. 169. Campbell EM, Nonneman D, Rohrer GA. Fine mapping a quantitative trait locus affecting ovulation rate in swine on chromosome 8. Journal of Animal Science. 2003; 81(7): 1706–1714.
  170. 170. Bidanel JP, Rosendo A, Iannuccelli N, Riquet J, Gilbert H, Caritez JC, Billon Y, Amigues Y, Prunier A, Milan D. Detection of quantitative trait loci for teat number and female reproductive traits in Meishan × Large White F2 pigs. Animal. 2008; 2(6): 813-820.
  171. 171. Schneider JF, Nonneman DJ, Wiedmann RT, Vallet JL, Rohrer GA. Genomewide association and identification of candidate genes for ovulation rate in swine. Journal of Animal Science. 2014; 92(9): 3792-803.
  172. 172. Rothschild MF, Messer L, Day A, Wales R, Short T, Southwood O, Plastow G. Investigation of the retinol-binding protein 4 (RBP4) gene as a candidate gene for increased litter size in pigs. Mammalian Genome. 2000; 11(1): 75–77.
  173. 173. Jiang Z, Gibson JP, Archibald AL, Haley CS. The porcine gonadotropin-releasing hormone receptor gene (GNRHR): Genomic organization, polymorphisms, and association with the number of corpora lutea. Genome. 2001; 44(1): 7–12.
  174. 174. Korwin-Kossakowska A, Kamyczek M, Cieslak D, Pierzchala M, Kuryl J. The effect of the polymorphism of leptin (LEP), leptin receptor (LEPR) and osteopontin (OPN) genes on selected reproduction traits of synthetic Line 990 sows. Animal Science Papers and Reports. 2002; 20(3): 159–168.
  175. 175. Vallet JL, Freking BA, Leymaster KA, Christenson RK. Allelic variation in the secreted folate binding protein gene is associated with uterine capacity in swine. Journal of Animal Science. 2005; 83(8): 1860–1867.
  176. 176. Spötter A, Hamann H, Müller S, Distl O. Effect of polymorphisms in four candidate genes for fertility on litter size in a german pig line. Reproduction in Domestic Animals. 2010; 45(4): 579–584.
  177. 177. Peiró R, Herrler A, Santacreu MA, Merchán M, Argente MJ, García ML, Folch JM, Blasco A. Expression of progesterone receptor related to the polymorphism in the PGR gene in the rabbit reproductive tract. Journal of Animal Science. 2010; 88: 421-427.
  178. 178. Argente MJ, Merchán M, Peiró R, García ML, Santacreu MA, Folch JM, Blasco A. Candidate gene analysis for reproductive traits in two lines of rabbits divergently selected for uterine capacity. Journal of Animal Science. 2010; 88(3): 828-836.
  179. 179. García ML, Peiró R, Argente MJ, Merchán M, Folch JM, Blasco A, Santacreu MA. Investigation of the oviductal glycoprotein 1 (OVGP1) gene associated with embryo survival and development in the rabbit. Journal of Animal Science. 2010; 88(5): 1597-1602.
  180. 180. Estellé J, Sastre Y, Merchán M, Peiró R, Santacreu MA, Folch JM. TIMP-1 as candidate gene for embryo survival in two divergent lines selected for uterine capacity in rabbits. Molecular Reproduction and Development. 2006; 73: 678-684.
  181. 181. Ballester M, Castelló A, Peiró R, Argente MJ, Santacreu MA, Folch JM. Identification of differentially expressed genes in the oviduct of two rabbit lines divergently selected for uterine capacity using suppression subtractive hybridization. Animal Genetic. 2013; 44: 296-304.
  182. 182. Caetano AR, Johnson RK, Ford JJ, Pomp D. Microarray profiling for differential gene expression in ovaries and ovarian follicles of pigs selected for increased ovulation rate. Genetics. 2004; 168: 1529-1537.
  183. 183. Fernandez-Rodriguez A, Muñoz M, Fernandez A, Pena RN, Tomas A, Noguera JL, Ovilo C, Fernandez AI. Differential gene expression in ovaries of pregnant pigs with high and low prolificacy levels and identification of candidate genes for litter size. Biology of Reproduction. 2011; 84(2): 299–307.
  184. 184. Østrup E, Bauersachs S, Blum H, Wolf E, Hyttel P. Differential endometrial gene expression in pregnant and nonpregnant sows. Biology of Reproduction. 2010; 83(2): 277-285.
  185. 185. Kim M, Seo H, Choi Y, Shim J, Kim H, Lee CK, Ka H. Microarray analysis of gene expression in the uterine endometrium during the implantation period in pigs. Asian-Australasian Journal of Animal Sciences. 2012; 25(8): 1102-1116.
  186. 186. Samborski A, Graf A, Krebs S, Kessler B, Bauersachs S. Deep sequencing of the porcine endometrial transcriptome on day 14 of pregnancy. Biology of Reproduction. 2013; 88(4): 84.
  187. 187. Samborski A, Graf A, Krebs S, Kessler B, Reichenbach M, Reichenbach HD, Ulbrich SE, Bauersachs S. Transcriptome changes in the porcine endometrium during the preattachment phase. Biology of Reproduction. 2013; 89(6): 134.
  188. 188. Franczak A, Wojciechowicz B, Kotwica G. Transcriptomic analysis of the porcine endometrium during early pregnancy and the estrous cycle. Reproduction of Biology. 2013; 13(3): 229-237.
  189. 189. Gu T, Zhu MJ, Schroyen M, Qu L, Nettleton D, Kuhar D, Lunney JK, Ross JW, Zhao SH, Tuggle CK. Endometrial gene expression profiling in pregnant Meishan and Yorkshire pigs on day 12 of gestation. BMC Genomics. 2014; 15: 156.
  190. 190. Su L, Liu R, Cheng W, Zhu M, Li X, Zhao S, Yu M. Expression patterns of MicroRNAs in Porcine endometrium and their potential roles in embryo implantation and placentation. PLoS ONE. 2014; 9(2): e87867.
  191. 191. Chen X, Li A, Chen W, Wei J, Fu J, Wang A. Differential gene expression in uterine endometrium during implantation in pigs. Biology of Reproduction. 2015; 92(2): 52.
  192. 192. Franczak A, Wojciechowicz B, Kolakowska J, Zglejc K, Kotwica G. Transcriptomic analysis of the myometrium during peri-implantation period and luteolysis–The study on the pig model. Functional & Integrative Genomics. 2014; 14(4): 673-682.

Written By

María-José Argente

Submitted: May 25th, 2015 Reviewed: January 22nd, 2016 Published: March 23rd, 2016