A list of eight retina-specific enhancers. The 8 retina-specific enhancers selected from the VISTA Enhancer Browser are listed above. They are grouped into 3 sub-groups according to the reporter expression in mouse embryos derived from these enhancers and the expression pattern of their flanking genes. The enhancer IDs, their expression pattern and the flanking gene names were retrieved directly from VISTA Enhancer Browser, with an expression pattern described as ‘tissue type (positive sample number/total sample number)’. Flanking genes with expression in the retina are shown in bold.
1. Introduction
The formation of the neatly layered retina during embryonic development is dictated by a series of complicated transcription factor interactions. Retina-specific expression of these transcription factors is an essential step in establishing retinal progenitor cells (RPCs) from embryonic stem cells. The transcriptional control of gene expression is largely mediated by the combinatorial interactions between
Identifying tissue/cell-specific
Currently, the prevailing method of studying TFBSs and transcriptional regulatory networks is to determine the function of tissue-specific trans-acting factors based on data from genome-wide gene expression profiling and chromatin immunoprecipitation (ChIP). ChIP is often used to investigate protein-DNA interactions in a cell. Coupled with massive parallel sequencing, ChIP-seq is capable of mapping the genome-wide protein-DNA interaction at a finer resolution (Valouev et al., 2008) to identify candidate enhancer sequences (Visel et al., 2009). Thus, a regulatory cascade can be recognized via consequential analysis of the factors involved.
Here, we present a new method for the computational analysis of TFBSs and transcriptional regulatory networks utilizing genome-wide sequencing, expression, and enhancer data. In contrast to the traditional method, which mainly focuses on factor expression analysis, we emphasize the sequence elements with tissue-specific enhancer activity. Our hypothesis is that enhancers, non-coding sequences that direct gene expression in a cell-/tissue-specific manner, contain common TFBSs that allow the key protein factors (important for the development of that cell/tissue type) to bind. Experimentally verified tissue-specific enhancer elements selected from enhancer databases were carefully screened for common trans-acting factor binding sites to predict potential sequence-factor interacting networks. DNA-binding protein factors that associate with multiple enhancers can be analyzed using experimental methods.
As proof-of-principle, simple transcriptional regulatory networks of embryonic retinal development were assembled based on common/key factors and their interacting genes, as determined by literature search. These resulting networks provide a general view of embryonic retinal development and a new hypothesis for further experimentation.
2. Methods and results
In this study, we aimed to develop a method for the identification of regulatory networks for cell/tissue-specific gene expression. To test our hypothesis of the existence of common TFBSs on the enhancers of cell/tissue specific genes, we employ the mouse developing retina as a model system. Enhancers that direct retina-specific gene expression were selected and their sequences were thoroughly screened for common TFBSs and
2.1. Retina-specific enhancers
To determine the transcriptional regulatory networks that govern retinal development, we identified and selected enhancer elements that direct gene expression in the retina by searching the VISTA Enhancer Browser. The VISTA Enhancer Browser is a central resource for experimentally validated human and mouse non-coding DNA fragments with enhancer activity as assessed in transgenic mice. Most of these non-coding elements were selected for testing based on their extreme conservation in other vertebrates or epigenomic evidence (ChIP-Seq) of putative enhancer marks. The results of this
Group | Enhancer ID | Length (bp) |
Reporter expression pattern derived from enhancer activity | Annotation of reporter expression | Flanking genes of enhancers and their endogenous expression in mouse embryos | |
Upstream | Downstream | |||||
1 |
|
1113 | eye(4/6), limb(4/6) | Retina + non-CNS |
|
|
|
1487 | eye(3/5), limb, | Retina + non-CNS | Ccdc39: E14.5 |
|
|
|
1753 | eye(7/7), limb, nose | Retina + non-CNS |
|
Arrdc3: E14-19 | |
|
1288 | eye(8/8) | Retina |
|
Arrdc3: E14-19 | |
2 |
|
775 | eye(6/9), limb, nose, branchial arch | Retina + non-CNS | AA408296: unknown | Irf6: not in retina |
|
926 | eye(4/5), heart | Retina + non-CNS | Lao1: unknown | Slc2a1: not in retina | |
3 |
|
1218 | eye(6/7) | Retina+ Spinal cord |
|
Pah: not in retina |
|
760 | eye(5/5), heart, other | Retina+ Spinal cord |
|
2.2. Trans -acting factor binding sites on retina-specific enhancers
The binding of trans-acting factors (e.g., transcription factors) to non-coding regulatory DNA (e.g., promoters, enhancers, etc.) is an essential process in the control of gene expression. This protein-DNA interaction helps recruit the DNA polymerase complex and co-activators to form the transcription machinery. The binding of these protein factors can also act as repressors to prevent transcription. Identification of a TFBS in the enhancer and promoter for a gene may indicate the possibility that the corresponding factors play a role in the regulation of that gene. Importantly, the ability of an enhancer to direct cell/tissue-specific gene expression is achieved via the binding of tissue-specific
2.3. A motif containing Pou3f2 binding sites
Since all 8 enhancers possess the ability to direct retina-specific gene expression, there may be key TFBSs shared amongst these retina-specific sequence elements. To test this hypothesis, we sorted and screened the TFBSs of each of the 8 enhancers to identify common ones using a Matlab program that we developed for this study (Supporting data 6). This Matlab program for common TFBS selection was designed to compare the TFBSs on each of the retina-specific enhancer elements predicted by TESS. TFBSs for two or three different enhancers can be sequentially compared. A “model” character was used as the comparison category instead of the binding site name in both TESS and our Matlab program. As defined in TESS, a model is “the site string or weight matrix used to pick this site” (Schug, 2002), and thus describes the nature of a binding site. One factor may have multiple models, and one model may be shared by multiple factors. The model character is the only necessary parameter to characterize the transcription factors depending on their binding site property.
With this sorting/searching program, we identified a TFBS for Pou3f2 (also known as Brn2) that was present in all 8 retina-specific enhancers (Fig. 1A). Previous studies have demonstrated that the Pou3f2 transcription factor plays an important role in the development of neural progenitor cells (Catena et al., 2004; Kim et al., 2008b; McEvilly et al., 2002; Sugitani et al., 2002). Furthermore, the literature reports that this motif was first discovered as a
We thus speculate that this Pou3f2 binding site may exist in regulatory sequences among genes important for the development of neural retinal progenitor cells (RPCs). Therefore, the
2.4. Key trans -acting factors involved in transcriptional regulatory networks of retinal development
It is unlikely that only one factor (i.e., Pou3f2) is involved in regulating retina-specific gene expression.
Key TFBSs should be common to all or a subset of retina-specific enhancer elements;
The flanking genes of these enhancer elements should be expressed in the retina during early retinal development, because an enhancer often regulates the expression of its flanking gene(s);
The binding factors should have a known function in retinal development, or
If the binding factors have an unknown function in retinal development, they should be at least expressed in the retina during retinal development. In this case, the expression of the factor provides novel hypothesis for their function in retinal development, which needs to be tested by functional studies.
Based on the above assumptions, the information on the expression of the flanking genes of enhancer elements in the developing retina is necessary for the TFBS analysis. Five databases of gene expression (see Table 2) were searched. The information on the expression of these flanking genes were retrieved from these databases (Tables 1, 4 and supporting data 3). The factors that do not express in the retina during embryonic retinal development, e.g., around E11.5 (when enhancer elements were active), were set aside for further analysis of retinal transcriptional regulatory networks. We then searched common TFBSs among subsets of the 8 retina-specific enhancers. The TFBSs common to individual different sub-groups were combined. In addition to Pou3f2, five other factors (i.e., Crx, Hes1, Meis1, Pbx2, and Tcf3) were identified (Table 3). Four of the 6 factors have known functions in retinal development, which is consistent with our hypothesis. The last two factors do not have known functions in the retina. However, the prediction of their binding with groups of enhancers suggests they play a role during retinogenesis. As the binding sites of these 6 factors were shared among a subset of retina-specific enhancer elements, these 6 binding
Database | Source | Reference |
Gene expression database (emage) of Edinburg Mouse Atlas Project (EMAP, v5.0_3.3) | http://www.emouseatlas.org/emage/ | (Richardson et al., 2010) |
Gene Expression Database in Mouse Genome Informatics (MGI, version 4.4) | http://www.informatics.jax.org | (Finger et al., 2011) |
Eurexpress | http://www.eurexpress.org | (Diez-Roux et al., 2011) |
VisiGene Image Browser | http://genome.ucsc.edu/cgi-bin/hgVisiGene | (Kent et al., 2002) |
Genome-scale mouse brain transcription factor expression analysis | Supplementary data S4 and S6 | (Gray et al., 2004) |
Factor | Binding site | Known function | Expression pattern | Presence in enhancer element |
Pou3f2 | ATTTGCAT | Induce Bipolar cells | E10.5-14.5 in retina; diencephalon, future midbrain, future SC, rhombencephalon | All 8 elements |
Crx | tgaggGGATCAAcagact | Induce Photoreceptors | E11-adult in retina | hs27, hs258, hs546, hs1170 |
Hes1 | CTTGTG | Repress Amacrine, Horizontal, and Ganglion cells; Induce Photoreceptors |
E11-13 in retina, thalamus, hypothalamus, striatum, olfactory epithelial | hs27, hs258, hs1170 |
Meis1 | CTGTCActaagatgaca | retinal cell fate determination | E10.5-14.5 in retina, lens vesicle, diencephalon, future sc, hindbrain | hs27, hs258, hs546, hs1170, hs932, mm165 |
Pbx-2 | cacctgagagTGACAGaaggaaggcagggag | No function known in retina | E10.5-14.5 in retina, thalamus, midbrain, hindbrain, sc, ear | hs27, hs258, hs546, hs1170, hs932, mm165 |
Tcf3 | ccaccagCACCTGtc | No function known in retina | E13.5 in retina (MGI) | hs27, hs258, hs546, hs1170 |
Gene | Function (related to retina development) and reference |
Ascl1 | With Mash3, regulate the neuron/glia fate determination (Hatakeyama et al., 2001); with Mahs3 and Chx10, specify Biopolar cell identity (Satow et al., 2001). |
Irx5 | Off circuit subsets of bipolar interneuron (Cheng et al., 2005; Cohen et al., 2000; Kerschensteiner et al., 2008). |
Irx6 | No known clear function in retina. But It expresses in the in the area lining the lumen of the otic vesicle including the region giving rise to ganglion complex of CN VII/VIII at E11.5 through E16.5 and overlaps with Mash1 (Cohen et al., 2000; Mummenhoff et al., 2001) |
Fxr1 | Retina pigmentation(de Diego Otero et al., 2000); other function not known. |
Nr2f1 | Amacrine development, may involve in cone differentiation; express in a unique gradient in retina along D/V axis (Inoue et al., 2010). |
Zfand5 | No known function in retina. |
Interestingly, three common TFBSs (i.e., Pou3f2, Crx, and Meis1) were present among enhancer elements hs27, hs258, and hs1170 (see Tables 1, 3). Sequence alignment of the three enhancer elements and
Meis1 together with Meis2, as members of the TALE-homeodomain protein Homothorax (Hth) related protein family, were known to be expressed in the RPCs of mouse and chick (Heine et al., 2008). Meis1 was expressed in RPCs throughout the entire neurogenesis period, and Meis2 was expressed more specifically in RPCs before the initiation of retina differentiation. Together, they function to maintain the RPCs in a rapid proliferating state and control the expression of other ocular genes, e.g., Pax6, CyclinD1, Six3 and Chx10 (Bessa et al., 2008; Heine et al., 2008). Since Meis1 binding sites are present in a subset of retina-specific enhancers, Meis1 may function as an RPC-specific factor. Since the onset of mouse retina neurogenesis is approximately at E10.5 when the ganglion cells first appear (Leo M. Chalupa, 2008). By E11.5, RPCs of all six cell types are highly active. Therefore, binding of Meis1 with enhancers might influence the cell fate of these RPCs.
The presence of common Pbx2 binding sites may indicate a novel functional role of Pbx2 in RPCs, since the function of Pbx2 in retinal development has not been documented. Previous studies have shown that Pbx2 is expressed in the zebrafish retina and tectum (French et al., 2007) together with Pbx1 and Meis1, and down-regulation in their expression caused by the deficiency of Prep, the prolyl endopeptidase will lead to eye anomalies (Deflorian et al., 2004; Ferretti et al., 2006). Pbx and Meis proteins are major DNA-binding partners that form abundant complexes (Chang et al., 1997). Thus, there is a possibility that Pbx2 may function in the development of RPCs via the interaction with Meis1 and also regulate other RPC-specific genes (e.g., Irx5, Nr2f1, etc) through enhancer binding (Table 1).
Tcf3 is not yet known to have a function in embryonic retinal development. However, since Tcf3 binding sites are present among the retina-specific enhancer elements, and Tcf3 is expressed in the retina during embryogenesis, its specific function in retinal development needs to be confirmed.
2.5. Generation of transcriptional regulatory network for early retinal development
Based on the available expression data from VISTA Enhancer Browser and gene expression databases (Table 2), it is known that these 8 enhancer elements and their common binding
Retina-specific gene expression is most likely determined by two kinds of interactions: (1) the enhancers with their binding protein factors, and (2) the protein factors with their interacting partners. The information about these interactions was used to generate the transcriptional regulatory networks important for retinal development. Therefore, transcriptional regulatory networks of embryonic retina were predicted based on these 6 common/key
To construct retinal transcriptional regulatory networks, a java-based software program named BioTapestry (Longabaugh et al., 2009) (http://www.biotapestry.org/, version 5.0.2) was used to organize the factors and their known interacting partners. BioTapestry is a network facilitating software program designed for dealing with systems that exhibit increasingly complex over time, such as genetic regulatory networks. Its unique annotation system allows the illustration of enhancer-regulated gene expression and connection between factors. Experimental evidence can also be added to network elements after the network was built, as a proof of particular interactions. We only used the presenting function of BioTapestry here to show the networks of retinal development during early neurogenesis. For better illustration, the network was mapped according to the 3-layer structure of the mouse retina.
Based on the published information on the interacting factors of these 6
Factor name | Reference cited |
Cabp5 | (Kim et al., 2008a) |
Chx10 | (Hatakeyama et al., 2001) |
CyclinD1 | (Bessa et al., 2008; Heine et al., 2008) |
Foxn4 | (Shengguo Li, 2004) |
Grk1 | (Young and Young, 2007) |
Grmb | (Kim et al., 2008a) |
Hes6 | (Bae et al., 2000) |
Mash3 | (Hatakeyama et al., 2001; Satow et al., 2001) |
Math5 | (Lee et al., 2005) |
Nestin | (Rowan and Cepko, 2005) |
NeuroD1 | (Conte et al., 2010) |
Nr2f1 | (Inoue et al., 2010; Satoh et al., 2009) |
Otx2 | (Kim et al., 2008a; Young and Young, 2007) |
Pax6 | (Ferretti et al., 2006; Lee et al., 2005; Oliver et al., 1995) |
Prep1 | (Deflorian et al., 2004; Ferretti et al., 2006) |
Rax | (Heine et al., 2008; Martinez-de Luna et al., 2010) |
Six3 | (Oliver et al., 1995) |
Six6 | (Conte et al., 2010) |
In summary, the computational method we developed in this study can be described as following. First, experimentally verified enhancer elements can be selected from enhancer databases, e.g., the Vista Enhancer Browser, based on tissue/cell-specific expression patterns derived from the enhancer element and its flanking gene (Fig. 4A-A). These tissue-specific enhancer elements can be located in the non-coding regions in inter- or intra- genetic sequences. Then, the
3. Conclusion
In this study we have explored a new way of using existing TFBS-finding methods to predict
Acknowledgments
This work is supported in part by grants (EY018738 and EY019094) from the National Institute of Health, the New Jersey Commission on Spinal Cord Research (10A-003-SCR1 and 08-3074-SCR-E-0), and Busch Biomedical Research Awards (6-49121). The authors thank the Cai lab members for helpful discussions and for proof-reading the manuscript.
References
- 1.
Bae S. Bessho Y. Hojo M. Kageyama R. 2000 The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development127 2933 2943 - 2.
Bailey T. L. Elkan C. 1994 Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc Int Conf Intell Syst Mol Biol2 28 36 - 3.
Bessa J. Tavares M. J. Santos J. Kikuta H. Laplante M. Becker T. S. Gómez-Skarmeta J. L. Casares F. 2008 meis1 regulates cyclin D1 and c-myc expression, and controls the proliferation of the multipotent cells in the early developing zebrafish eye. Development135 799 803 - 4.
Cartharius K. Frech K. Grote K. Klocke B. Haltmeier M. Klingenhoff A. Frisch M. Bayerlein M. Werner T. 2005 MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics21 2933 2942 - 5.
Catena R. Tiveron C. Ronchi A. Porta S. Ferri A. Tatangelo L. Cavallaro M. Favaro R. Ottolenghi S. Reinbold R. et al. 2004 Conserved POU binding DNA sites in the Sox2 upstream enhancer regulate gene expression in embryonic and neural stem cells. J Biol Chem279 41846 41857 - 6.
Chang C. Jacobs Y. Nakamura T. Jenkins N. Copeland N. Cleary M. 1997 Meis proteins are major in vivo DNA binding partners for wild-type but not chimeric Pbx proteins. Mol Cell Biol17 5679 5687 - 7.
Cheng C. W. Chow R. L. Lebel M. Sakuma R. Cheung H. O. L. Thanabalasingham V. Zhang X. Bruneau B. G. Birch D. G. Hui C.-c. et al. 2005 The Iroquois homeobox gene, Irx5, is required for retinal cone bipolar cell development. Developmental Biology287 48 60 - 8.
Cohen D. R. Cheng C. W. Cheng S. H. Hui C.-c. 2000 Expression of two novel mouse Iroquois homeobox genes during neurogenesis. Mechanisms of Development91 317 321 - 9.
Conte, I., Marco-Ferreres, R., Beccari, L., Cisneros, E., Ruiz, J.M., Tabanera, N., and Bovolenta, P. (2010 ). Proper differentiation of photoreceptors and amacrine cells depends on a regulatory loop between NeuroD and Six6. Development 137, 2307-2317 - 10.
Corbo J. C. Lawrence K. A. Karlstetter M. Myers C. A. Abdelaziz M. Dirkes W. Weigelt K. Seifert M. Benes V. Fritsche L. G. et al. 2010 CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors. Genome Res20 1512 1525 - 11.
de Diego Otero. Y. Bakker C. Raghoe P. Severijnen L. A. Hoogeveen A. Oostra B. Willemsen R. 2000 Immunocytochemical characterization of FMRP, FXR1P and FXR2P during embryonic development in the mouse. Gene Function & Disease1 28 37 - 12.
Deflorian G. Tiso N. Ferretti E. Meyer D. Blasi F. Bortolussi M. Argenton F. 2004 Prep1.1 has essential genetic functions in hindbrain development and cranial neural crest cell differentiation. Development131 613 627 - 13.
Diez-Roux G. Banfi S. Sultan M. Geffers L. Anand S. Rozado D. Magen A. Canidio E. Pagani M. Peluso I. et al. 2011 A high-resolution anatomical atlas of the transcriptome in the mouse embryo. , e1000582. - 14.
Ferretti E. Villaescusa J. C. Di Rosa P. Fernandez-Diaz L. C. Longobardi E. Mazzieri R. Miccio A. Micali N. Selleri L. Ferrari G. et al. 2006 Hypomorphic Mutation of the TALE Gene Prep1 (pKnox1) Causes a Major Reduction of Pbx and Meis Proteins and a Pleiotropic Embryonic Phenotype. Mol Cell Biol26 5650 5662 - 15.
Finger, J.H., Smith, C.M., Hayamizu, T.F., McCright, I.J., Eppig, J.T., Kadin, J.A., Richardson, J.E., and Ringwald, M. (2011 ). The mouse Gene Expression Database (GXD): 2011 update. Nucleic Acids Research 39, D835-D841 - 16.
Frazer K. A. Pachter L. Poliakov A. Rubin E. M. Dubchak I. 2004 VISTA: computational tools for comparative genomics. , W273 W279. - 17.
French C. R. Erickson T. Callander D. Berry K. M. Koss R. Hagey D. W. Stout J. Wuennenberg-Stapleton K. Ngai J. Moens C. B. et al. 2007 Pbx homeodomain proteins pattern both the zebrafish retina and tectum. , 85. - 18.
Gray, P.A., Fu, H., Luo, P., Zhao, Q., Yu, J., Ferrari, A., Tenzen, T., Yuk, D.I., Tsung, E.F., Cai, Z., et al. (2004 ). Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306, 2255-2257 - 19.
Hatakeyama J. Tomita K. Inoue T. Kageyama R. 2001 Roles of homeobox and bHLH genes in specification of a retinal cell type. Development128 1313 1322 - 20.
Heine P. Dohle E. Bumsted-O’Brien K. Engelkamp D. Schulte D. 2008 Evidence for an evolutionary conserved role of homothorax/Meis1/2 during vertebrate retina development. Development135 805 811 - 21.
Hsiau T. H. Diaconu C. Myers C. A. Lee J. Cepko C. L. Corbo J. C. 2007 The cis-regulatory logic of the mammalian photoreceptor transcriptional network., e643. - 22.
Hu, J., Wan, J., Hackler, L., Jr., Zack, D.J., and Qian, J. (2010 ). Computational analysis of tissue-specific gene networks: application to murine retinal functional studies. Bioinformatics 26, 2289-2297 - 23.
Inoue M. Iida A. Satoh S. Kodama T. Watanabe S. 2010 COUP-TFI and-TFII nuclear receptors are expressed in amacrine cells and play roles in regulating the differentiation of retinal progenitor cells. Experimental Eye Research90 49 56 - 24.
Kent W. J. Sugnet C. W. Furey T. S. Roskin K. M. Pringle T. H. Zahler A. M. and Haussler. D. 2002 The human genome browser at UCSC. Genome Res12 996 1006 - 25.
Kerschensteiner, D., Liu, H., Cheng, C.W., Demas, J., Cheng, S.H., Hui, C.-c., Chow, R.L., and Wong, R.O.L. (2008 ). Genetic Control of Circuit Function: Vsx1 and Irx5 Transcription Factors Regulate Contrast Adaptation in the Mouse Retina. J Neurosci 28, 2342-2352 - 26.
Kim D. S. Matsuda T. Cepko C. L. 2008a A Core Paired-Type and POU Homeodomain-Containing Transcription Factor Program Drives Retinal Bipolar Cell Gene Expression. J Neurosci28 7748 7764 - 27.
Kim D. S. Matsuda T. Cepko C. L. 2008b A core paired-type and POU homeodomain-containing transcription factor program drives retinal bipolar cell gene expression. J Neurosci28 7748 7764 - 28.
Knuppel R. Dietze P. Lehnberg W. Frech K. Wingender E. 1994 TRANSFAC retrieval program: a network model database of eukaryotic transcription regulating sequences and proteins. Journal of computational biology : a journal of computational molecular cell biology1 191 198 - 29.
Kumar J. P. 2009 The molecular circuitry governing retinal determination. Biochim Biophys Acta1789 306 314 - 30.
Le T. T. Wroblewski E. Patel S. Riesenberg A. N. Brown N. L. 2006 Math5 is required for both early retinal neuron differentiation and cell cycle progression. Developmental Biology295 764 778 - 31.
Lee H. Y. Wroblewski E. Philips G. T. Stair C. N. Conley K. Reedy M. Mastick G. S. Brown N. L. 2005 Multiple requirements for Hes1 during early eye formation. Developmental Biology284 464 478 - 32.
Leo M. Chalupa R. W. W. 2008 (The MIT Press). - 33.
Longabaugh W. J. R. Davidson E. H. Bolouri H. 2009 Visualization, documentation, analysis, and communication of large-scale gene regulatory networks. Biochimica et Biophysica Acta (BBA)- Gene Regulatory Mechanisms1789 363 374 - 34.
Martinez-de Luna. R. I. Moose H. E. Kelly L. E. Nekkalapudi S. El -Hodiri H. M. 2010 Regulation of retinal homeobox gene transcription by cooperative activity among cis-elements. Gene467 13 24 - 35.
Mc Evilly R. J. de Diaz M. O. Schonemann M. D. Hooshmand F. Rosenfeld M. G. 2002 Transcriptional regulation of cortical neuron migration by POU domain factors. Science295 1528 1532 - 36.
Mummenhoff J. Houweling A. C. Peters T. Christoffels V. M. Rüther U. 2001 Expression of Irx6 during mouse morphogenesis. Mechanisms of Development103 193 195 - 37.
Oliver G. Mailhos A. Wehr R. Copeland N. G. Jenkins N. A. Gruss P. 1995 Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development121 4045 4055 - 38.
Peng G. H. Ahmad O. Ahmad F. Liu J. Chen S. 2005 The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes. Human Molecular Genetics14 747 764 - 39.
Portales-Casamar, E., Thongjuea, S., Kwon, A.T., Arenillas, D., Zhao, X., Valen, E., Yusuf, D., Lenhard, B., Wasserman, W.W., and Sandelin, A. (2010 ). JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles. Nucleic Acids Research 38, D105-110 - 40.
Richardson, L., Venkataraman, S., Stevenson, P., Yang, Y., Burton, N., Rao, J., Fisher, M., Baldock, R.A., Davidson, D.R., and Christiansen, J.H. (2010 ). EMAGE mouse embryo spatial gene expression database: 2010 update. Nucleic Acids Research 38, D703-D709 - 41.
Rowan S. Cepko C. L. 2005 A POU factor binding site upstream of the Chx10 homeobox gene is required for Chx10 expression in subsets of retinal progenitor cells and bipolar cells. Developmental Biology281 240 255 - 42.
Sandelin A. Alkema W. Engstrom P. Wasserman W. W. Lenhard B. 2004 JASPAR: an open-access database for eukaryotic transcription factor binding profiles. , D91 94 - 43.
Satoh S. Tang K. Iida A. Inoue M. Kodama T. Tsai S. Y. Tsai M. J. Furuta Y. Watanabe S. 2009 The Spatial Patterning of Mouse Cone Opsin Expression Is Regulated by Bone Morphogenetic Protein Signaling through Downstream Effector COUP-TF Nuclear Receptors. J Neurosci29 12401 12411 - 44.
Satow T. Bae S. K. Inoue T. Inoue C. Miyoshi G. Tomita K. Bessho Y. Hashimoto N. Kageyama R. 2001 The Basic Helix-Loop-Helix Gene hesr2 Promotes Gliogenesis in Mouse Retina.21 1265 1273 - 45.
Schug J. 2002 Using TESS to Predict Transcription Factor Binding Sites in DNA Sequence (John Wiley & Sons, Inc.). - 46.
Shengguo Li. Z. M. Xuejie Yang. 2004 Foxn4 Controls the Genesis of Amacrine and Horizontal Cells by Retinal Progenitors. Neuron43 795 807 - 47.
Sicinski P. Donaher J. L. Parker S. B. Li T. Fazeli A. Gardner H. Haslam . S. Z. Bronson R. T. Elledge S. J. Weinberg R. A. 1995 Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell82 621 630 - 48.
Sugitani Y. Nakai S. Minowa O. Nishi M. Jishage K. Kawano H. Mori K. Ogawa M. Noda T. 2002 Brn-1 and Brn-2 share crucial roles in the production and positioning of mouse neocortical neurons. Genes Dev16 1760 1765 - 49.
Swaroop A. Kim D. Forrest D. 2010 Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci11 563 576 - 50.
Tang K. Xie X. Park J. I. Jamrich M. Tsai S. Tsai M. J. 2010 COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development137 725 734 - 51.
Valouev A. Johnson D. S. Sundquist A. Medina C. Anton E. Batzoglou S. Myers R. M. Sidow A. 2008 Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nat Meth5 829 834 - 52.
Visel A. Blow M. J. Li Z. Zhang T. Akiyama J. A. Holt A. Plajzer-Frick I. Shoukry M. Wright C. Chen F. et al. 2009 ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature457 854 858 - 53.
Visel A. Minovitsky S. Dubchak I. Pennacchio L. A. 2007 VISTA Enhancer Browser-a database of tissue-specific human enhancers. , D88 D92. - 54.
Wall D. S. Mears A. J. Mc Neill B. Mazerolle C. Thurig S. Wang Y. Kageyama R. Wallace V. A. 2009 Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity. J Cell Biol184 101 112 - 55.
Young J. E. Kasperek E. M. Vogt T. M. Lis A. Khani S. C. 2007 Conserved interactions of a compact highly active enhancer/promoter upstream of the rhodopsin kinase (GRK1) gene. Genomics90 236 248