Open access peer-reviewed chapter - ONLINE FIRST

Signaling Pathways Regulating Axogenesis and Dendritogenesis in Sympathetic Neurons

Written By

Vidya Chandrasekaran

Submitted: December 25th, 2021Reviewed: January 3rd, 2022Published: January 23rd, 2022

DOI: 10.5772/intechopen.102442

Autonomic Nervous System - Special Interest TopicsEdited by Theodoros Aslanidis

From the Edited Volume

Autonomic Nervous System - Special Interest Topics [Working Title]

Dr. Theodoros Aslanidis and M.Sc. Christos Nouris

Chapter metrics overview

65 Chapter Downloads

View Full Metrics


The post-ganglionic sympathetic neurons play an important role in modulating visceral functions and maintaining homeostasis through complex and reproducible axonal and dendritic connections between individual neurons and with their target tissues. Disruptions in these connections and in sympathetic nervous system function are observed in several neurological, cardiac and immune-related disorders, which underscores the need for understanding the mechanisms underlying neuronal polarity, axonal growth and dendritic growth in these neurons. The goals of this chapter are to explore our current understanding of the various growth factors, their signaling pathways, downstream effectors and interplay between these pathways to regulate different stages of axonal and dendritic growth in sympathetic neurons.


  • sympathetic neurons
  • growth factors
  • neurotrophins
  • cytokines
  • BMPs
  • axons
  • dendrites

1. Introduction

The sympathetic nervous system is an important component of the peripheral autonomic nervous system responsible for controlling the visceral functions of the body to maintain homeostasis and the “flight or fight response” [1]. The sympathetic pathway is composed of two neurons – a preganglionic neurons located in the intermediolateral horn of the spinal cord, originating from the thoracolumbar region of the spinal cord and the postganglionic neuron that is, in most cases, located in the paravertebral sympathetic ganglia chain on either side of the spinal cord. Some of the preganglionic axons synapse with pre-vertebral sympathetic ganglia such as the celiac, mesenteric and pelvic ganglia, which innervate the gastrointestinal and urinary tracts and are not part of the sympathetic chain [2]. The superior cervical ganglia (SCG) is the first and the largest ganglia in the sympathetic chain and innervates most of the tissues in the head and neck region including the pineal gland, cerebral blood vessels, carotid body, vestibular system, muscles in the iris, lacrimal glands and piloerector muscles. Of the sympathetic neurons, SCG neurons are one of the most studied to understand various aspects of neuronal development in the peripheral nervous system. In recent years, the observation of autonomic dysfunction in many diseases such as Parkinson’s disease, cardiac disorders, multiple system atrophy, multiple sclerosis, diabetes and immune-related disorders, has renewed an interest in understanding neuronal development and maintenance of sympathetic neurons [3, 4, 5, 6, 7, 8, 9, 10, 11].

During early development, the precursors of the post-ganglionic sympathetic neurons are derived from the trunk neural crest cells, which then migrate ventrally along the neural tube, through the anterior portion of the sclerotome and coalesce near the dorsal aorta to form the sympathetic ganglia [12]. In rodents, the neural crest migration occurs between E8 and E11, with cells forming coalesced sympathetic ganglia around E12–E14 with the more rostral ganglia forming before the caudal ones. Studies on the early sympathetic neuron specification and neural crest migration show that growth factors such as neurotrophins, semaphorins and ephrins are important for migration of these neural crest cells, with bone morphogenetic proteins (BMPs) being important for their differentiation into sympathetic neuronal lineage. The exposure to BMPs leads to the induction o of transcription factors such as Phox2b, Mash1, Hand2, Gata3, Insm1, Sox4 and Sox 11, which lead to the survival of these neurons and their differentiation into noradrenergic neurons [12]. Following the specification of these neurons, the next crucial step to create a functional sympathetic network is the extension and maturation of axons and dendrites. In this chapter, we will explore the pathways that are important for establishing and refining axonal and dendritic arbors in sympathetic neurons.


2. Growth factors and signaling pathways involved in axonal growth

Following the specification of sympathetic neurons, the first sign of neuronal polarity is the extension of a single axon from the cell body [13]. In rodents, although the initiation of axonal growth from sympathetic ganglia starts as early as E12, most of the axonal growth occurs around E14–E15, with target innervation continuing into first few weeks of postnatal life [13, 14, 15]. Axonal growth has three stages – initiation of axons from the post-ganglionic neurons, elongation of the axons towards the final targets and finally target innervation which involves branching as well as restriction of axonal growth. Research using cultured sympathetic neurons in vitroand in vivostudies have identified multiple growth factors, extracellular matrix molecules and downstream signaling targets, involved in different stages of axonal growth and axonal guidance, functioning either as activators or inhibitors of axonal growth. In this section, we will examine the various molecules and their roles in these three stages of axonal growth.

2.1 Hepatocyte growth factor

Hepatocyte growth factor (HGF) or scatter factor is one of the few growth factors that appears to be involved in initiation of axonal growth in sympathetic neurons. Both HGF and its receptor Met tyrosine kinase are co-expressed in the sympathetic neurons throughout embryonic, starting as early as E12.5, with HGF being secreted by the sympathetic neurons and functioning as an autocrine regulator of axonal growth [16, 17, 18]. Treatment of cultured sympathetic neurons with HGF induces axonal growth and enhances the axonal growth promoted by nerve growth factor [16]. Also, inhibition of HGF activity through treatment with anti-HGF antibodies and Metsignaling mutants show decreased axonal growth and branching compared to wildtype embryos [17, 18, 19]. Although HGF promotes survival of sympathetic neuroblasts, it is not necessary for the survival of post-mitotic sympathetic neurons [17]. Furthermore, in vitrostudies and studies on docking site mutants for Met receptors suggest that HGF exerts its effects on axonal growth in mice through activation of the mitogen-activated protein kinase (MAPK) pathway and PI-3 K pathway [20]. Although lack of HGF signaling in vivoresults in decreased axonal growth, it does not lead complete lack of axons in sympathetic neurons, suggesting the involvement of other factors in the first step of axonal growth.

2.2 Artemin

Artemin, a member of the glial derived neurotrophic factor (GDNF) family ligands (GFLs) plays an important role in the axonal elongation and guidance of the postganglionic axons to their targets [21, 22, 23, 24]. In addition to Artemin, other members of the GDNF family, including GDNF and Nerturin have been shown to enhance neurite growth in subpopulations of sympathetic neurons [21, 22, 24] Artemin mRNA is expressed at high levels near the dorsal aorta around E12.5 and then in the smooth muscles of many of the blood vessels along which the sympathetic axons migrate to their targets [25, 26]. The receptors for Artemin – Ret and GFRa3 are both expressed in the sympathetic ganglia as early as E11.5 and then expression gets restricted to subsets of cells later in embryonic development [26, 27, 28, 29]. Treatment of nascent sympathetic ganglia (E13.5) with artemin induces axonal growth with axons showing branching and radial outgrowth. Also, axonal growth from explant cultures of the ganglia are directed towards beads coated with artemin, suggesting artemin has the ability to guide axons to their targets [30]. In addition, Artemin knockout mice show decreased axonal growth postnatally, [31] and mice lacking either GFRa3 or Ret show reduced, depleted or abnormal neuronal projections and abnormal branching indicating that Artemin signaling mediated by Ret:GFRa3 receptor complex is necessary for proper migration of sympathetic neurons during development [26, 28]. Although early studies suggest a role for Artemin in sympathetic neuron survival with the superior cervical ganglia being smaller in Artemin, Ret and GFRα3 knockout animals compared to wild type animals [29, 32], more recent studies suggest that the decreased neuronal cell numbers in the absence of Artemin signaling are an indirect effect of aberrant axonal migration and target innervation [28]. Taken together, the data suggest that the members of the GDNF family act as early guidance molecules to promote axon elongation and target innervation.

2.3 Neurotrophins

Neurotrophin family of growth factors – nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) and brain derived neurotrophic factor (BDNF) have been implicated in many aspects of neuronal function, including differentiation, survival, axonal growth and dendritic growth [33, 34, 35, 36, 37]. These neurotrophins are synthesized and secreted as proneurotrophins, which are the proteolytically cleaved to generate mature neurotrophins that activate different isoforms of Trk tyrosine kinase receptors (Trk) and p75 neurotrophin receptors (p75NTR) and activate a variety of downstream signaling pathways [33, 34, 35, 36, 38].

2.3.1 Nerve growth factor

NGF synthesis begins in targets of sympathetic neurons in concert with the arrival of the sympathetic axons and is correlated with increased expression of TrkA [39, 40, 41, 42, 43]. Although NGF is necessary for survival for sympathetic neurons in the early stages, the neurons lose their dependence on NGF for survival in the later stages in vivoand in vitro[42, 44, 45]. Exposure of sympathetic neurons to exogenous NGF, overexpression of NGF in the target tissues or adding NGF to compartments containing the distal axons leads to increased axonal growth and hyperinnervation of the target tissues [46, 47, 48, 49, 50, 51]. Conversely, mice lacking NGF or TrkA (NGF receptor) show decreased survival of sympathetic neurons and decreased target innervation [52, 53, 54]. In addition to NGF, proNGF promotes axonal elongation and branching in postnatal sympathetic neurons through activation of the p75NTR receptor rather than the TrkA receptor [55].

NGF’s axonal growth effects are independent of its effects on neuronal survival. Mice lacking both NGF and Bax, a pro-apoptotic gene necessary for apoptosis in sympathetic neurons [56, 57], show normal early axonal growth and guidance along the vasculature but show differential loss of innervations in the different target tissues with sympathetic innervation being completely absent in salivary glands and cardiac ventricles, reduced in the liver and unaffected in the trachea [58]. These evidence supports the argument that NGF is important for axon growth of the distal axons and target innervation. It is interesting to note that this requirement for target-derived NGF in the terminal axonal growth varies between the different targets, suggesting that other growth factors are important for target innervation in some of these tissue [58].

NGF’s effects on axonal growth are primarily mediated through activation of the TrkA receptors. NGF and phosphorylated TrkA are retrogradely transported in endosomes from the axon terminals [59, 60, 61, 62] and regulate axonal growth through changes to cytoskeletal proteins and transcription factors such as cyclic AMP response element binding protein (CREB) and early growth regulator 3 (Egr3) [49, 63, 64, 65, 66, 67]. Also, local reintroduction of NGF to NGF-deprived neurons in culture results in profuse axonal growth, suggesting that NGF promotes axonal growth both locally and through retrograde signaling [68]. NGF also upregulates the expression of its receptor TrkA in sympathetic neurons [41] and activates downstream effectors such as PI-3Kinase-Akt pathways and MAPK pathways leading to cytoskeletal changes resulting in axonal growth [69]. In addition, NGF, through its binding to TrkA receptors, activates glycogen synthase kinase-3 (GSK-3), which results in the phosphorylation of microtubule-associated protein 1B (MAP1B) and decrease in MAP1B phosphorylation is correlated with decreased axonal growth [70]. NGF signaling during axonal elongation and termination is dependent on activation SHP-2, a protein tyrosine phosphatase. Inhibition of SHP-2 in vitroleads to decreased axonal growth by inhibiting extracellular signal-regulated kinase (ERK) signaling, however interfering with SHP-2 signaling results in increased axonal density within the targets [71]. Also, studies suggest that Wnt 5a is upregulated in sympathetic targets in response to NGF, and blocking Wnt5a activation using an antibody suppresses NGF-induced axonal growth [72]. Early growth response (Egr) proteins – Egr1 and Egr3 are induced by NGF signaling in sympathetic neurons with inhibition of Egr1 in vitrousing a dominant negative and Egr3 knockout in vivoshow decreased neurite outgrowth and target innervation [49, 73, 74]. Recent studies have suggest a role of non-coding RNAs and post-translational modifications downstream of NGF signaling during axonal growth [75, 76]. Untranslated axonal mRNA Tp53inp2 upregulates NGF-TrkA signaling during axonal growth [75] and NGF-dependent prenylation of proteins such as Rac GTPase appears to be important for receptor trafficking to promote axonal growth [76].

Once the axons reach the target, NGF-TrkA signaling increases the expression of Coronin-1, a protein that interacts with the actin cytoskeleton [77]. Coronin-1 acts as a molecular switch to convert downstream effectors of NGF-TrkA from the PI-3 K pathway to calcium signaling, leading to the suppression of axonal growth and branching [77, 78].

2.3.2 Neurotrophin 3 (NT-3)

In addition to NGF, neurotrophin-3 is expressed in sympathetic neurons, although its main receptor TrkC is expressed at low levels in neonatal sympathetic neurons [44, 79, 80, 81]. NT-3 mutant mice show severe defects in their sympathetic nervous system with 50% fewer neurons, and defects in axonal branching and axonal innervation of target tissues such as the pineal gland and cardiac myocytes [82, 83, 84]. In addition, neurotrophin-3 (NT-3) promotes axonal growth and branching in sympathetic neurons in vitro[41, 84]. Overexpression of NT-3 in adipose tissue leads to increased sympathetic innervation through its activation of TrkC receptors [85]. However, NT-3’s effects on axonal growth are mediated by activation of TrkA receptors as opposed to TrkC, with NT-3 selectively promoting neurite outgrowth rather than for survival in neonatal sympathetic neurons [41]. Although both NGF and NT-3 signal using the same receptor, unlike the NGF-TrkA complex, NT-3-TrkA complex does not mediate retrograde signaling [61]. Recent studies also suggest that NT3-TrkA complex prevents axons from branching into intermediate targets and enables larger growth cones in the absence of Coronin-1, through activation of Ras-MAPK and PI3K-Akt pathways [86].

2.3.3 Brain-derived neurotrophic factor (BDNF)

Similar to other neurotrophins, BDNF is expressed in sympathetic neurons and sympathetic neuron targets [79, 87], and serves as target-derived growth factor for pre-ganglionic sympathetic neurons [88]. Unlike NGF and NT-3, BDNF null mutants show a slight increase in the number of sympathetic neurons compared to wildtype animals, indicating that BDNF is not important for survival of sympathetic neurons [89]. Addition of exogenous BDNF inhibits axonal growth and inhibiting BDNF activity using antibodies against BDNF promotes axonal growth in sympathetic neurons in vitro[79]. Also, BDNF +/− and BDNF −/− mice show hyperinnervation of the target tissues [87]. Although Trk B (the main BDNF receptor) is not present in sympathetic neurons [41], the sympathetic axons express p75NTR during target innervation [87] and BDNF’s effects on axonal growth are mediated through its interaction with this receptor. BDNF-p75NTR signaling inhibits the activity of NGF-TrkA complex leading to axonal growth inhibition in vitroand axon pruning in vivo[87, 90].

2.4 Tumor necrosis factor superfamily

Multiple members of the tumor necrosis factor superfamily (TNFSF) are known to regulate axonal growth in sympathetic neurons. Members of the TNFSF act as either as membrane-bound ligands or soluble ligands once cleaved from the membrane and bind to receptors belonging to the TNF superfamily (TNFRSF) [91, 92]. These molecules can also serve as reverse signaling molecules with TNFRSF acting as ligands and membrane-bound TNFSF functioning as receptors [93].

TNFa protein is present in postnatal SCG neurons throughout the cell body and neurites with strong immunoreactivity for TNF receptors R1 (TNFR1) in the cell body and in target tissues [94]. tnfa−/−and tnfr−/−mice show decreased innervation of sympathetic targets, with no effect on neuronal numbers [94]. While soluble TNFa inhibits NGF-induced axonal growth in vitrothrough activation of NF-kB [95], the reverse signaling mediated by TNFR1 at the axon terminal enhances axonal growth and target innervation through elevation of opening of T-type calcium channels leading to rapid activation of protein kinase C, ERK1 and ERK2 [94, 96]. Another TNF superfamily member – receptor-activator of NF-κB (RANK, also known as TNFRSF11A)) is expressed in embryonic and early postnatal sympathetic neurons, while its ligand RANKL is expressed in target tissues [97]. Similar to TNFa, local activation of RANKL-RANK signaling is necessary for axonal growth effects, and addition of soluble RANKL or activation of RANK signaling inhibits NGF-induced axonal extension and branching, through activation of NF-κB signaling [97]. The glucocorticoid induced tumor necrosis factor receptor related protein (GITR) and its ligand GITRL are also expressed in sympathetic neurons [98]. The activation of GITR by its ligand GITRL leads to activation of ERK signaling and the downregulation of NF-kB signaling pathways and regulation of both of these pathways are necessary for NGF-induced axonal growth [98, 99]. A recent study showed that TWE-PRIL, an alternative spliced form that combines extracellular domain of one TNFSF member APRIL (TNFSF13) and the transmembrane and cytoplasmic domains of another member TWEAK (TNFSF12), is expressed in developing SCG neurons [100]. April−/− mice show increased axonal growth in the presence of NGF, that can be rescued by overexpression of TWE-PRIL. TWE-PRIL reverse signaling leads to axonal growth inhibition by preventing NGF-dependent activation of ERK [100]. Similarly, CD40 (TNFRSF5) and its ligand CD40L are expressed in embryonic and early postnatal SCG neurons [101]. While CD40 by itself does not affect axonal growth, the reverse autocrine signaling mediated by CD40-CD40L enhances NGF induced axonal growth in these neurons, especially when there is low NGF with high levels of NGF inhibiting CD40 and CD40L expression [102].

Interestingly, two TNF family members have differential effects on paravertebral and prevertebral ganglia. Unlike SCG targets which showed hypoinnervation in tnfa−/−and tnfr−/−mice, the targets of the prevertebral sympathetic ganglia showed no change in innervation and reverse signaling mediated by TNFR1 did not alter axonal growth from prevertebral ganglia neurons [103]. Similarly, CD40 null mutants show hyperinnervation in targets of prevertebral ganglia and CD40-CD40L reverse signaling inhibits axonal growth in prevertebral ganglia neurons [101].

2.5 Extracellular matrix proteins

As axons extend from the sympathetic ganglia to the target, they are exposed to a complex environment composed of extracellular matrix molecules such as laminin, collagen, fibronectin and thrombospondin. Laminin, collagen IV and thrombospondin promote axonal growth in perinatal superior cervical ganglia neurons in vitroand mediate their effects on axonal growth through activation of specific classes of integrin receptors [104, 105, 106, 107]. Exposure of SCG neurons to laminin leads to formation of multiple axons, whereas neurons exposed to collagen IV extend only a single axon suggesting distinct signaling pathways downstream of integrin activation [104, 105, 108]. In addition, exposure to laminin causes bundling of microtubules, leading to rapidly growing axons [109]. Conversely, chondroitin sulfate proteoglycans inhibit axonal growth in cultured neonatal SCG neurons and may be responsible for lack of sympathetic reinnervation of the heart during ischemia-reperfusion injury [110].

2.6 Other signaling pathways involved in axonal growth

Interleukin 1b (IL-1b) and Interleukin 1 receptor (IL-1R) are expressed in neonatal sympathetic neurons with IL-1R1 being present in the cell body and axons, and IL-1b being expressed in the sympathetic neurons and target tissues [111, 112]. IL-1b inhibits axonal growth in cultured sympathetic neurons by promoting the nuclear translocation of NF-kB [112].

Ceramide, a lipid second messenger, generated from glycosphingolipid metabolism or sphingomyelin metabolism is known to be important for cell proliferation or cell death downstream of extracellular agents such as TNF, interleukins and other molecules [113, 114]. Although newly synthesized glycosphingolipids are not important for axonal growth, when added to the distal axons ceramide inhibits neuronal outgrowth, possibly by decreasing the uptake of NGF by the distal axons [113, 114].


3. Growth factors and signaling pathways involved in dendritic growth regulation

Dendritogenesis in post-ganglionic sympathetic neurons begins around E14, with maturation of dendritic arbor continuing into postnatal development [13, 115]. Sympathetic neurons extend multiple dendrites with complex branching patterns. The size of the dendritic arbor is dependent on size of the target field and neuronal activity, suggesting that dendritic complexity is determined by the needs of the targets [116, 117, 118, 119, 120]. Similar to axonal growth, dendritogenesis can be divided into 3 stages – initiation of dendrites, elongation and branching of dendrites, and maturation coupled with pruning of the dendritic tree. In this section, we will explore the current understanding of the various growth factors, their signaling pathways and interactions between them to influence dendritic arborization in sympathetic neurons.

3.1 Bone morphogenetic proteins (BMPs)

Members of the bone morphogenetic protein (BMP) family are important for dendritic growth initiation in sympathetic neurons in vitroand in vivo.BMPs bind and activate a heterotrimeric receptor complex of transmembrane serine/threonine kinase receptors made of type I receptor – BMP receptor type I A (BMPR1a), also known as activin receptor-like kinase-3 (ALK-3) or BMP receptor type IB (BMPR1b), also known as ALK-6, and one of the three type II receptors – BMPRII, Activin type II or IIB (Act II or ActRIIB). The activation of these kinases leads to phosphorylation of receptor Smads (Smads 1, 5 and/or 8), which complex with Smad 4 to translocate to the nucleus and regulate gene expression [121, 122, 123].

Sympathetic neurons and glial cells in the SCG from embryonic and postnatal ganglia express mRNA and protein for BMP-5, BMP-6 and BMP-7 [108, 124, 125]. Also, BMPR1a, BMPRIIB, ActRII and BMPRII are present in mouse SCG through later stages of embryonic development into postnatal life [126, 127], suggesting that BMP signaling pathway is functional in sympathetic neurons during periods of dendritogenesis. BMP-5, BMP-6, BMP-7 initiate dendritic growth in cultured perinatal sympathetic neurons by activation and translocation of the Smad complex and regulating gene expression [108, 128, 129]. Conditional knockouts of BMPR1a or both BMPR1a/1b show a decrease in dendritic length and branch complexity compared to congenic wildtype animals but do not show complete absence of dendrites [130]. Also, BMP receptor knockouts showed a dramatic decrease in total dendritic length, branching and soma size later in postnatal development suggesting that BMP signaling may be important for maintenance of dendrites, rather than initiation of dendrites in vivo[130]. This difference in BMP function in vitroand in vivomay stem from the presence of other receptors such as the activin receptors to mediate BMP signaling [131]. Interestingly, although transfection of Smad1 dominant negative mutant blocks BMP-7-induced dendritic growth in vitro, the SCG neurons in conditional Smad 4 knockout mice show an increase in dendritic length and total dendritic arbor [130], suggesting that Smad 4 may play a limiting role in vivoand BMPs may be signaling through Smad-dependent and Smad-independent pathways for dendritic growth regulation.

Transcriptome and miRNome analyses have identified over 250 genes and over 40 microRNAs whose expression are altered in response to BMP-7 treatment in cultured sympathetic neurons during the period of dendritic growth initiation [132, 133]. Of the genes, p75NTR mRNA and protein are strongly upregulated by BMP-7 signaling in cultured SCG neurons. BMP-mediated effects on dendritic growth are not observed in p75NTR knockout mice, with p75NTR knockout mice showing stunted dendritic arbor compared to wildtype. Conversely, overexpression of p75NTR phenocopies the dendritic growth effects of BMP-7, suggesting that this is an important target of BMP-7 during dendritic growth regulation [132, 134]. However, p75NTR ligands, interplay between neurotrophins and BMP in activating p75NTR and downstream effectors of p75NTR signaling responsible for dendritogenesis in sympathetic neurons still need to be elucidated. Of the microRNAs identified, three miRNAs – miR-21, miR-23b and miR-664-1* may regulate dendritic growth downstream of BMP-7 in sympathetic neurons in vitro[133]. Also, signaling pathways mediated by ubiquitin-proteasome system and by reactive oxygen species are suggested to be downstream of Smad signaling in sympathetic neurons in vitrowith proteasome inhibitors and antioxidants inhibiting BMP-7 induced dendritic growth [135, 136].

3.2 Neuronal activity dependent dendritic growth

Electric field stimulation or treatment of sympathetic neurons with potassium chloride can lead to neuronal depolarization and this neuronal activity triggers dendritic growth in postganglionic sympathetic neurons by the activation of calcium calmodulin dependent kinase II (CaMKII) [137]. Also, inhibition of integrin-linked kinase (ILK) using an siRNA prevents activity-dependent dendritic growth in sympathetic neurons in vitro, whereas pharmacological inhibition of glycogen synthase kinase-3β (GSK-3β) enhances activity-dependent dendritic growth in these neurons [138, 139].

3.3 Nerve growth factor and fibroblast growth factor

NGF was one of the earliest growth factors recognized as important for dendritic growth with NGF injections leading to enhanced dendritic growth in sympathetic ganglia [116]. However, NGF, by itself, is unable to induce dendritic growth in cultured perinatal SCG neurons, but is required for BMP-7 induced dendritic growth [129, 140]. One of the downstream targets of NGF for dendritic growth appears to be Egr3 with Egr3−/− mice showing significant decrease in the number of primary dendrites, total dendritic length and maximum extent of dendritic arbor [74].

Fibroblast growth factor receptor 1 (FGFR1) is expressed in adult SCG neurons and its nuclear localization increases in perinatal sympathetic neurons upon BMP-7 exposure [141, 142]. Also, expression of mutant FGFR1 decreases the dendritic growth induced by BMP-7 in sympathetic neurons, through the activation of the integrative nuclear FGFR1 signaling pathway [142].

Interestingly, stimulation of the MAPK signaling pathways has differential effects on activity-dependent dendritic growth and BMP-7 induced dendritic growth. While pharmacological inhibition of ERK activity using PD98059 inhibits activity-dependent dendritic growth, the treatment with the same inhibitor enhances BMP-7-induced dendritic growth [137, 139, 143]. Stimulation of the MAPK signaling through overexpression of MEK1 leads to inhibition of BMP-7 induced dendritic growth and the inhibition of MAPK signaling pathway with dominant negative MEK1 or ERK2 mutant increases the number of dendrites and total dendritic arbor in BMP-7 treated [143]. Further studies are needed to understand the opposing roles of ERK in BMP-induced vs. activity-dependent dendritic growth.

3.4 Cytokines

Several members of the cytokine family have been shown to regulate dendritic growth in sympathetic neurons. These growth factors function through the activation of the Janus kinase (JAK), leading to the nuclear translocation of proteins known as signal transducers and activators of transcription (STAT) [144]. In perinatal sympathetic neurons, interferons gamma (IFNg), leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) decrease the number of primary dendrites and total dendritic arbor, without affecting axonal growth and neuronal survival. In addition, these cytokines can lead to retraction of pre-existing dendrites through the activation of STAT proteins [145, 146, 147]. In addition to activating STATs, IFNg activates Rit, (a small GTPase related to Ras GTPase) and p38-MAPK pathway to effect the dendritic retraction observed in these neurons [148]. Rit is expressed in sympathetic neurons and has opposite effects on axonal and dendritic growth. Dominant negative Rit transgenes decrease axonal elongation but enhance BMP-7 induced dendritic growth in an ERK-signaling dependent manner and constitutively active Rit enhances number of axons and axonal branching in sympathetic neurons while inhibiting dendritic growth [149].

3.5 Cytoskeletal proteins

Dendritic growth and remodeling requires changes to the actin and microtubule cytoskeleton ([150, 151]. Signaling pathways downstream of Rho GTPases act as intermediates to connect extracellular signals and actin cytoskeletal remodeling during dendritic growth [152]. In cultured sympathetic neurons, BMP-7 treatment increases the GTP bound RhoA [153] and decreases GTP-bound Rit [149], with no effects on other small GTPases. In cultured SCG neurons, BMP-7 induced dendritic growth requires the activation of RhoA [153], suggesting that activation of this GTPase may be the link to actin cytoskeleton remodeling necessary for dendritic growth.

The microtubule polarity in axons is different from that in dendrites. Unlike microtubules in axons, which have a uniform polarity, microtubules in dendrites have a mixed orientation that is driven by the different motor proteins [154, 155]. A kinesin related motor protein kinesin 6 (also known as CHO/MKLP1) mRNA and protein are expressed in cultured embryonic sympathetic neuron, with CHO/MKLP1 protein extending from the cell body to the newly formed dendrites [156, 157]. Two other kinesin related motors – Kinesin 5 (also known as Eg5 or Kif11) and kinesin 12 (also known as Kif15) – are also expressed in embryonic sympathetic neurons [158, 159], with kinesin 5 associating only with the microtubule cytoskeleton and kinesin 12 being enriched in the dendrites and associating with both actin and microtubule cytoskeleton [158, 159, 160]. Treatment with antisense oligonucleotides against kinesin 6 lead to an increase in axonal length but a decrease in dendritic width and inhibition of BMP-7- induced dendritic growth in these neurons [156, 157]. Knockdown of kinesin 12 in cultured embryonic SCG neurons using an siRNA lead to longer axons that are less branched than control neurons and decrease in dendritic width [157, 160]. Both kinesin 6 and 12 appear to be important for the mixed polarity of microtubules in the dendrites with a decrease in these kinesins leading t0 fewer minus-end directed microtubules in the dendrites and increased frequency of microtubule transport. Similar to the others kinesins, inhibition of kinesin 5 leads to increase in axonal length, however a decrease in kinesin5 also leads to axons being non-responsive to navigational cues [161, 162]. In addition to a decrease in dendritic width like other kinesins, a reduction in kinesin 5 causes a decrease in dendritic length, a small decrease in number of dendrites and a significant effect on dendritic morphology especially during dendritic maturation stages [163]. In contrast to other kinesin mutants, a decrease in kinesin 5 leads to more minus-end microtubules in the dendrites [163]. Interestingly, kinesin5 appears to be regulated by phosphorylation with more phosphorylated kinesin5 being localized to the dendrites, suggesting that kinesin5 could be a potential link between signaling pathways and the cytoskeletal remodeling during dendritogenesis [163].

3.6 Other signaling pathways involved in dendritic growth

Retinoic acid synthesis enzymes and signaling pathway components are expressed in embryonic sympathetic neurons and activation of retinoic acid signaling in embryonic SCG neurons in vitroinhibits BMP-7 induced dendritic growth [164]. Similarly, pituitary adenylate cyclase 38(PACAP 38) and vasoactive intestinal peptide (VIP) are released by the preganglionic neurons and in cultured perinatal sympathetic neurons, PACAP38 and VIP decrease the number of dendrites and the total dendritic arbor of BMP-7 treated neurons. This effect is mediated through activation of the PAC1 receptor leading to the phosphorylation and nuclear translocation of cyclic AMP response element binding (CREB) protein, with inhibition of adenylate cyclase activity leading to enhanced dendritic growth [165].


4. Limitations of current research and the path forward

Sympathetic neurons have been long regarded as an important model system for studying neuronal differentiation. Due to increased recognition of the importance of sympathetic nervous system dysregulation in many diseases, there has been a renewed interest in understanding the mechanisms controlling neuronal differentiation, target innervation and neuronal survival in these neurons. Significant strides have been made in understanding axonal growth over the past 70 years in vitro and in vivobut there are still questions that need further exploration. While we understand the importance of individual growth factors for axonal growth, many of the null mutants show some innervation of target tissues. That still leaves the question of how much each of these growth factors contribute to initiation and elongation of axons during normal development and how their signaling pathways are coordinated to regulate final axonal growth in different paravertebral and prevertebral ganglia.

In comparison to axonal growth, our understanding of dendritic growth in these neurons is much more limited. Most of the studies on sympathetic neurons have been limited to cultured SCG neurons, which leaves the question of whether similar signals are important for regulation of dendritic growth in other paravertebral and prevertebral ganglia. Even in the SCG, many disparate signaling pathways including BMP, NGF, cytokine, ROS, ubiquitin-proteasome, etc. have been shown to control the dendritic tree in vitro.However, it is unclear which of these interactions are crucial for dendritic arborization in vivoin the SCG and how these pathways coordinately regulate dendritogenesis.

Finally, additional whole genome analysis looking at transcripts, proteins and non-coding RNAs is needed to fully understand the downstream mediators of both axogenesis and dendritogenesis to identify the common regulators controlling neuronal polarity and function in these neurons.



This work was supported through Saint Mary’s College internal research funding through Faculty Development Fund and Summer Research Fund.


  1. 1.Goldstein DS. Differential responses of components of the autonomic nervous system. Handbook of Clinical Neurology. 2013;117:13-22
  2. 2.Espinosa-Medina I, Saha O, Boismoreau F, et al. The sacral autonomic outflow is sympathetic. Science. 2016;354:893-897
  3. 3.Merola A, Romagnolo A, Rosso M, et al. Autonomic dysfunction in Parkinson’s disease: A prospective cohort study. Movement Disorders. 2018;33:391-397
  4. 4.Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G. Dysautonomias: Clinical disorders of the autonomic nervous system. Annals of Internal Medicine. 2002;137:753
  5. 5.Chu CC, Tranel D, Damasio AR, et al. The autonomic-related cortex: pathology in Alzheimer’s disease. Cereb Cortex. 1997;7:86-95
  6. 6.Jensen-Dahm C, Waldemar G, Staehelin Jensen T, et al. Autonomic dysfunction in patients with mild to moderate Alzheimer’s disease. Journal of Alzheimer’s Disease. 2015;47:681-689
  7. 7.Vinik AI, Maser RE, Mitchell BD, et al. Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553-1579
  8. 8.Adamec I, Habek M. Autonomic dysfunction in multiple sclerosis. Clinical Neurology and Neurosurgery. 2013;115:S73-78. DOI: 10.1016/j.clineuro. 2013.09.026
  9. 9.Racosta JM, Kimpinski K. Autonomic dysfunction, immune regulation, and multiple sclerosis. Clinical Autonomic Research. 2016;26:23-31
  10. 10.Goldberger JJ, Arora R, Buckley U, et al. Autonomic nervous system dysfunction: JACC focus seminar. Journal of the American College of Cardiology. 2019;73:1189
  11. 11.Rafanelli M, Walsh K, Hamdan MH, et al. Autonomic dysfunction: Diagnosis and management. Handbook of Clinical Neurology. 2019;167:123-137
  12. 12.Chan WH, Anderson CR, Gonsalvez DG. From proliferation to target innervation: signaling molecules that direct sympathetic nervous system development. Cell and Tissue Research. 2018;372:171-193. DOI: 10.1007/ s00441-017-2693-x
  13. 13.Rubin E. Development of the rat superior cervical ganglion: Ganglion cell maturation. The Journal of Neuroscience. 1985;5:673-684
  14. 14.Rubin E. Development of the rat superior cervical ganglion: Ingrowth of preganglionic axons. The Journal of Neuroscience. 1985;5:685
  15. 15.Rubin E. Development of the rat superior cervical ganglion: Initial stages of synapse formation. The Journal of Neuroscience. 1985;5:697-704
  16. 16.Yang XM, Toma JG, Bamji SX, et al. Autocrine hepatocyte growth factor provides a local mechanism for promoting axonal growth. The Journal of Neuroscience. 1998;18:8369-8381
  17. 17.Maina F, Hilton MC, Andres R, et al. Multiple roles for hepatocyte growth factor in sympathetic neuron development. Neuron. 1998;20:835-846
  18. 18.Maina F, Klein R. Hepatocyte growth factor, a versatile signal for developing neurons. Nature Neuroscience. 1999;2:213-217
  19. 19.Maina F, Panté G, Helmbacher F, et al. Coupling met to specific pathways results in distinct developmental outcomes. Molecular Cell. 2001;7:1293-1306
  20. 20.Thompson J, Dolcet X, Hilton M, et al. HGF promotes survival and growth of maturing sympathetic neurons by PI-3 kinase- and MAP kinase-dependent mechanisms. Molecular and Cellular Neurosciences. 2004;27:441-452
  21. 21.Baloh RH, Enomoto H, Johnson EM, et al. The GDNF family ligands and receptors—Implications for neural development. Current Opinion in Neurobiology. 2000;10:103-110
  22. 22.Airaksinen MS, Saarma M. The GDNF family: Signalling, biological functions and therapeutic value. Nature Reviews Neuroscience. 2002;3:383-394
  23. 23.Miwa K, Lee JK, Takagishi Y, et al. Axon guidance of sympathetic neurons to cardiomyocytes by glial cell line-derived neurotrophic factor (GDNF). PLoS One. 2013;8:e65202
  24. 24.Ernsberger U. The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons. Cell and Tissue Research. 2008;333:353
  25. 25.Baloh RH, Tansey MG, Lampe PA, et al. Neurotrophic factors represent a heterogeneous group of Sanicola et al. Neuron. 1998;21:1291-1302
  26. 26.Enomoto H, Crawford PA, Gorodinsky A, et al. RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development. 2001;128:3963-3974
  27. 27.Forgie A, Doxakis E, Buj-Bello A, et al. Differences and developmental changes in the responsiveness of PNS neurons to GDNF and neurturin. Molecular and Cellular Neurosciences. 1999;13:430-440
  28. 28.Honma Y, Araki T, Gianino S, et al. Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron. 2002;35:267-282
  29. 29.Nishino J, Mochida K, Ohfuji Y, et al. GFR alpha3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion. Neuron. 1999;23:725-736
  30. 30.Yan H, Newgreen DF, Young HM. Developmental changes in neurite outgrowth responses of dorsal root and sympathetic ganglia to GDNF, neurturin, and artemin. Developmental Dynamics. 2003;227:395-401
  31. 31.Andres R, Forgie A, Wyatt S, et al. Multiple effects of artemin on sympathetic neurone generation, survival and growth. Development. 2001;128:3685-3695
  32. 32.Durbec P, Marcos-Gutierrez CV, Kilkenny C, et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature. 1996;381:789-793
  33. 33.Reichardt LF. Neurotrophin-regulated signalling pathways. Philosophical Transactions of the Royal Society B. 2006;361:1545
  34. 34.Skaper SD. Neurotrophic factors: An overview. Methods in Molecular Biology. 2018;1727:1-17
  35. 35.Huang EJ, Reichardt LF. Neurotrophins: Roles in neuronal development and function. Annual Review of Neuroscience. 2001;24:677
  36. 36.Davies AM. Neurotrophins giveth and they taketh away. Nature Neuroscience. 2008;11:627-628
  37. 37.Davies AM. Extracellular signals regulating sympathetic neuron survival and target innervation during development. Autonomic Neuroscience. 2009;151:39-45
  38. 38.Lee R, Kermani P, Teng KK, et al. Regulation of cell survival by secreted proneurotrophins. Science. 2001;294:1945-1948
  39. 39.Korsching S, Thoenen H. Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: Correlation with density of sympathetic innervation. Proceedings of the National Academy of Sciences of the United States of America. 1983;80:3513
  40. 40.Korsching S, Thoenen H. Developmental changes of nerve growth factor levels in sympathetic ganglia and their target organs. Developmental Biology. 1988;126:40-46
  41. 41.Belliveau DJ, Krivko I, Kohn J, et al. NGF and neurotrophin-3 both activate TrkA on sympathetic neurons but differentially regulate survival and neuritogenesis. The Journal of Cell Biology. 1997;136:375-388
  42. 42.Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987;237:1154-1162
  43. 43.Shooter EM. Early days of the nerve growth factor proteins. Annual Review of Neuroscience. 2001;24:601-629
  44. 44.Birren SJ, Lo L, Anderson DJ. Sympathetic neuroblasts undergo a developmental switch in trophic dependence. Development. 1993;119:597-610
  45. 45.Glebova NO, Ginty DD. Growth and survival signals controlling sympathetic nervous system development. Annual Review of Neuroscience. 2005;28:191-222
  46. 46.Unsicker K, Wiegandt H. Promotion of survival and neurite outgrowth of cultured peripheral neurons by exogenous lipids and detergents. Experimental Cell Research. 1988;178:377-389
  47. 47.Edwards RH, Rutter WJ, Hanahan D. Directed expression of NGF to pancreatic beta cells in transgenic mice leads to selective hyperinnervation of the islets. Cell. 1989;58:161-170
  48. 48.Hoyle GW, Mercer EH, Palmiter RD, et al. Expression of NGF in sympathetic neurons leads to excessive axon outgrowth from ganglia but decreased terminal innervation within tissues. Neuron. 1993;10:1019-1034
  49. 49.Eldredge LC, Gao XM, Quach DH, et al. Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice. Development. 2008;135:2949-2957
  50. 50.Campenot RB. Local control of neurite development by nerve growth factor. Proceedings of the National Academy of Sciences of the United States of America. 1977;74:4516-4519
  51. 51.Campenot RB. Development of sympathetic neurons in compartmentalized cultures. II. Local control of neurite survival by nerve growth factor. Developmental Biology. 1982;93:13-21
  52. 52.Smeyne RJ, Klein R, Schnapp A, et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature. 1994;368:246-249
  53. 53.Fagan AM, Zhang H, Landis S, et al. TrkA, but not TrkC, receptors are essential for survival of sympathetic neurons in vivo. The Journal of Neuroscience. 1996;16:6208-6218
  54. 54.Crowley C, Spencer SD, Nishimura MC, et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell. 1994;76:1001-1011
  55. 55.Howard L, Wyatt S, Nagappan G, et al. ProNGF promotes neurite growth from a subset of NGF-dependent neurons by a p75NTR-dependent mechanism. Development. 2013;140:2108-2117
  56. 56.Knudson CM, Tung KSK, Tourtellotte WG, et al. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 1995;270:96-99
  57. 57.Deckwerth TL, Elliott JL, Knudson CM, et al. BAX is required for neuronal death after trophic factor deprivation and during development. Neuron. 1996;17:401-411
  58. 58.Glebova NO, Ginty DD. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. The Journal of Neuroscience. 2004;24:743
  59. 59.Tsui-Pierchala BA, Ginty DD. Characterization of an NGF-P-TrkA retrograde-signaling complex and age-dependent regulation of TrkA phosphorylation in sympathetic neurons. The Journal of Neuroscience. 1999;19:8207-8218
  60. 60.Kuruvilla R, Zweifel LS, Glebova NO, et al. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell. 2004;118:243-255
  61. 61.Harrington AW, St. Hillaire C, Zweifel LS, et al. Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell. 2011;146:421
  62. 62.Ginty DD, Segal RA. Retrograde neurotrophin signaling: Trk-ing along the axon. Current Opinion in Neurobiology. 2002;12:268-274
  63. 63.Riccio A, Pierchala BA, Ciarallo CL, et al. An NGF-TrkA-mediated retrograde signal to transcription factor CREB in sympathetic neurons. Science. 1997;277:1097-1100
  64. 64.Cosker KE, Courchesne SL, Segal RA. Action in the axon: Generation and transport of signaling endosomes. Current Opinion in Neurobiology. 2008;18:270
  65. 65.MacInnis BL, Senger DL, Campenot RB. Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons. Neuropharmacology. 2003;45:995-1010
  66. 66.Campenot RB. NGF uptake and retrograde signaling mechanisms in sympathetic neurons in compartmented cultures. Results and Problems in Cell Differentiation. 2009;48:141-158
  67. 67.Howe CL, Mobley WC. Long-distance retrograde neurotrophic signaling. Current Opinion in Neurobiology. 2005;15:40-48
  68. 68.Campenot RB. Local control of neurite sprouting in cultured sympathetic neurons by nerve growth factor. Developmental Brain Research. 1987;37:293-301
  69. 69.Atwal JK, Massie B, Miller FD, et al. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron. 2000;27:265-277
  70. 70.Goold RG, Gordon-Weeks PR. NGF activates the phosphorylation of MAP1B by GSK3β through the TrkA receptor and not the p75NTR receptor. Journal of Neurochemistry. 2003;87:935-946
  71. 71.Chen B, Hammonds-Odie L, Perron J, et al. SHP-2 mediates target-regulated axonal termination and NGF-dependent Neurite growth in sympathetic neurons. Developmental Biology. 2002;252:170
  72. 72.Bodmer D, Levine-Wilkinson S, Richmond A, et al. Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympathetic neurons. The Journal of Neuroscience. 2009;29:7569-7581
  73. 73.Li L, Eldredge LC, Quach DH, et al. Egr3 dependent sympathetic target tissue innervation in the absence of neuron death. PLoS One. 2011;6:e2569. DOI: 10.1371/journal.pone.0025696
  74. 74.Quach DH, Oliveira-Fernandes M, Gruner KA, et al. A sympathetic neuron autonomous role for Egr3-mediated gene regulation in dendrite morphogenesis and target tissue innervation. The Journal of Neuroscience. 2013;33:4570
  75. 75.Crerar H, Scott-Solomon E, Bodkin-Clarke C, et al. Regulation of NGF signaling by an axonal Untranslated mRNA. Neuron. 2019;102:553-563
  76. 76.Scott-Solomon E, Kuruvilla R. Prenylation of axonally translated Rac1 controls NGF-dependent axon growth. Developmental Cell. 2020;53:691
  77. 77.Suo D, Park J, Harrington AW, et al. Coronin-1 is a neurotrophin endosomal effector that is required for developmental competition for survival. Nature Neuroscience. 2014;17:36-45. DOI: 10.1038/nn.3593
  78. 78.Suo X, Park J, Young S, et al. Coronin-1 and calcium signaling governs sympathetic final target innervation. The Journal of Neuroscience. 2015;35:3893-3902
  79. 79.Schecterson LC, Bothwell M. Novel roles for neurotrophins are suggested by BDNF and NT-3 mRNA expression in developing neurons. Neuron. 1992;9:449-463
  80. 80.Dechant G, Barde Y-A. The neurotrophin receptor p75NTR: Novel functions and implications for diseases of the nervous system. Nature Neuroscience. 2002;5:1131-1136
  81. 81.Dechant G, Rodriguez-Tebar A, Kolbeck R, et al. Specific high-affinity receptors for neurotrophin-3 on sympathetic neurons. The Journal of Neuroscience. 1993;13:2610-2616
  82. 82.Ernfors P, Lee KF, Kucera J, et al. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell. 1994;77:503-512
  83. 83.Fariñas I, Jones KR, Backus C, et al. Severe sensory and sympathetic deficits in mice lacking neurotrophin-3. Nature. 1994;369:658-661
  84. 84.Story GM, Dicarlo SE, Rodenbaugh DW, et al. Inactivation of one copy of the mouse neurotrophin-3 gene induces cardiac sympathetic deficits. Physiological Genomics. 2000;2(3):129-136
  85. 85.Cui X, Jing J, Wu R, et al. Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue. Nature Communications. 2021;12:5362. DOI: 10.1038/s41467-021-25766-2
  86. 86.Keeler AB, Suo D, Park J, et al. Delineating neurotrophin-3 dependent signaling pathways underlying sympathetic axon growth along intermediate targets. Molecular and Cellular Neurosciences. 2017;82:66
  87. 87.Kohn J, Aloyz RS, Toma JG, et al. Functionally antagonistic interactions between the TrkA and p75 neurotrophin receptors regulate sympathetic neuron growth and target innervation. The Journal of Neuroscience. 1999;19:5393-5408
  88. 88.Causing CG, Gloster A, Aloyz R, et al. Synaptic innervation density is regulated by neuron-derived BDNF. Neuron. 1997;18:257-267
  89. 89.Ernfors P, Kucera J, Lee KF, et al. Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice. The International Journal of Developmental Biology. 2003;39:799-807
  90. 90.Singh KK, Park KJ, Hong EJ, et al. Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration. Nature Neuroscience. 2008;11:649-658. DOI: 10.1038/nn.2114
  91. 91.Grivennikov SI, Kuprash DV, Liu ZG, et al. Intracellular signals and events activated by cytokines of the tumor necrosis factor superfamily: From simple paradigms to complex mechanisms. International Review of Cytology. 2006;252:129-161
  92. 92.Hehlgans T, Pfeffer K. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: Players, rules and the games. Immunology. 2005;115:1
  93. 93.Sun M, Fink PJ. A new class of reverse signaling costimulators belongs to the TNF family. Journal of Immunology. 2007;179:4307-4312
  94. 94.Kisiswa L, Osório C, Erice C, et al. TNFα reverse signaling promotes sympathetic axon growth and target innervation. Nature Neuroscience. 2013;16:865
  95. 95.Gutierrez H, O’Keeffe GW, Gavaldà N, et al. Nuclear factor κB signaling either stimulates or inhibits Neurite growth depending on the phosphorylation status of p65/RelA. The Journal of Neuroscience. 2008;28:8246
  96. 96.Kisiswa L, Erice C, Ferron L, et al. T-type Ca2+ channels are required for enhanced sympathetic axon growth by TNFα reverse signalling. Open Biology. 2017;7:160288. DOI: 10.1098/RSOB.160288
  97. 97.Gutierrez H, Kisiswa L, O’Keeffe GW, et al. Regulation of neurite growth by tumour necrosis superfamily member RANKL. Open Biology. 2013;3:120150. DOI: 10.1098/RSOB.120150
  98. 98.O’Keeffe GW, Gutierrez H, Pandolfi PP, et al. NGF-promoted axon growth and target innervation requires GITRL-GITR signaling. Nature Neuroscience. 2008;11:135-142
  99. 99.McKelvey L, Gutierrez H, Nocentini G, et al. The intracellular portion of GITR enhances NGF-promoted neurite growth through an inverse modulation of Erk and NF-κB signalling. Biology Open. 2012;1:1016-1023
  100. 100.Howard L, Wosnitzka E, Okakpu D, et al. TWE-PRIL reverse signalling suppresses sympathetic axon growth and tissue innervation. Development. 2018;145:dev165936. DOI: 10.1242/DEV.165936
  101. 101.Calhan OY, Wyatt S, Davies AM. CD40L reverse signaling suppresses prevertebral sympathetic axon growth and tissue innervation. Developmental Neurobiology. 2019;79:949-962
  102. 102.McWilliams TG, Howard L, Wyatt S, et al. Regulation of autocrine signaling in subsets of sympathetic NeuronsHas regional effects on tissue innervation. Cell Reports. 2015;10:1443
  103. 103.Erice C, Calhan OY, Kisiswa L, et al. Regional differences in the contributions of TNF reverse and forward signaling to the establishment of sympathetic innervation. Developmental Neurobiology. 2019;79:317
  104. 104.Lein PJ, Higgins D. Laminin and a basement membrane extract have different effects on axonal and dendritic outgrowth from embryonic rat sympathetic neurons in vitro. Developmental Biology. 1989;136:330-345
  105. 105.Lein PJ, Higgins D, Turner DC, et al. The NC1 domain of type IV collagen promotes axonal growth in sympathetic neurons through interaction with the alpha 1 beta 1 integrin. The Journal of Cell Biology. 1991;113:417-428
  106. 106.Osterhout DJ, Frazier WA, Higgins D. Thrombospondin promotes process outgrowth in neurons from the peripheral and central nervous systems. Developmental Biology. 1992;150:256-265
  107. 107.DeFreitas MF, Yoshida CK, Frazier WA, et al. Identification of integrin alpha 3 beta 1 as a neuronal thrombospondin receptor mediating neurite outgrowth. Neuron. 1995;15:333-343
  108. 108.Lein P, Guo X, Hedges AM, et al. The effects of extracellular matrix and osteogenic Protein-1 on the morphological differentiation of rat sympathetic neurons. International Journal of Developmental Neuroscience. 1996;14:203-215
  109. 109.Tang D, Goldberg DJ. Bundling of microtubules in the growth cone induced by laminin. Molecular and Cellular Neurosciences. 2000;15:303-313
  110. 110.Gardner RT, Habecker BA. Infarct-derived chondroitin sulfate proteoglycans prevent sympathetic Reinnervation after cardiac ischemia-reperfusion injury. The Journal of Neuroscience. 2013;33:7175
  111. 111.Bai Y, Hart RP. Cultured sympathetic neurons express functional interleukin-1 receptors. Journal of Neuroimmunology. 1998;91:43-54
  112. 112.Nolan AM, Nolan YM, O’Keeffe GW. IL-1β inhibits axonal growth of developing sympathetic neurons. Molecular and Cellular Neurosciences. 2011;48:142-150
  113. 113.De Chaves EP, Bussiere M, MacInnis B, et al. Ceramide inhibits axonal growth and nerve growth factor uptake without compromising the viability of sympathetic neurons. The Journal of Biological Chemistry. 2001;276:36207-36214
  114. 114.Posse de Chaves EI, Bussière M, Vance DE, et al. Elevation of ceramide within distal neurites inhibits neurite growth in cultured rat sympathetic neurons. Journal of Biological Chemistry. 1997;272:3028-3035. DOI: 10.1074/ jbc.272.5.3028
  115. 115.Voyvodic JT. Development and regulation of dendrites in the rat superior cervical ganglion. The Journal of Neuroscience. 1987;7:904-912
  116. 116.Snider WD. Nerve growth factor enhances dendritic arborization of sympathetic ganglion cells in developing mammals. The Journal of Neuroscience. 1988;8:2628-2634
  117. 117.Purves D, Hume RI. The relation of postsynaptic geometry to the number of presynaptic axons that innervate autonomic ganglion. The Journal of Neuroscience. 1981;1:441-452
  118. 118.Purves D, Hadley RD, Voyvodic JT. Dynamic changes in the dendritic geometry of individual neurons visualized over periods of up to three months in the superior cervical ganglion of living mice. The Journal of Neuroscience. 1986;6:1051-1060
  119. 119.Ruit KG, Osborne PA, Schmidt RE, et al. Nerve growth factor regulates sympathetic ganglion cell morphology and survival in the adult mouse. The Journal of Neuroscience. 1990;10:2412-2419
  120. 120.Chandrasekaran V, Lein PJ. Regulation of dendritogenesis in sympathetic neurons. In: Autonomic Nervous System. Rijeka: InTech; 2018. DOI: 10.5772/intechopen.80480
  121. 121.Katagiri T, Watabe T. Bone Morphogenetic Proteins. Cold Spring Harb Perspect Biology. 2016;8:a021899. DOI: 10.1101/cshperspect.a021899
  122. 122.Wotton D, Massague J. Transcriptional control by the TGF- b / Smad signaling system. The EMBO Journal. 2000;19:1745-1754
  123. 123.Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature. 2003;425:577-584
  124. 124.Guo X, Rueger D, Higgins D. Osteogenic protein-1 and related bone morphogenetic proteins regulate dendritic growth and the expression of microtubule-associated protein-2 in rat sympathetic neurons. Neuroscience Letters. 1998;245:131-134
  125. 125.Lein PJ, Beck HN, Chandrasekaran V, et al. Glia induce dendritic growth in cultured sympathetic neurons by modulating the balance between bone morphogenetic proteins (BMPs) and BMP antagonists. The Journal of Neuroscience. 2002;22:10377-10387
  126. 126.O’Keeffe GW, Gutierrez H, Howard L, et al. Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation. Neural Development. 2016;11:4
  127. 127.Zhang D, Mehler MF, Song Q, et al. Development of bone morphogenetic protein receptors in the nervous system and possible roles in regulating trkC expression. The Journal of Neuroscience. 1998;18:3314-3326
  128. 128.Beck HN, Drahushuk K, Jacoby DB, et al. Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons. BMC Neuroscience. 2001;2:12. DOI: 10.1186/1471-2202-2-12
  129. 129.Lein P, Johnson M, Guo X, et al. Osteogenic protein-1 induces dendritic growth in rat sympathetic neurons. Neuron. 1995;15:597-605
  130. 130.Majdazari A, Stubbusch J, Müller CM, et al. Dendrite complexity of sympathetic neurons is controlled during postnatal development by BMP signaling. The Journal of Neuroscience. 2013;33:15132-15144
  131. 131.Ten Dijke P, Hill CS. New insights into TGF-β–Smad signalling. Trends in Biochemical Sciences. 2004;29:265-273
  132. 132.Garred MM, Wang MM, Guo X, et al. Transcriptional responses of cultured rat sympathetic neurons during BMP-7-induced dendritic growth. PLoS One. 2011;6:e21754
  133. 133.Pravoverov K, Whiting K, Thapa S, et al. MicroRNAs are Necessary for BMP-7-induced Dendritic Growth in Cultured Rat Sympathetic Neurons. Cellular and Molecular Neurobiology. 2019;39:917-934. DOI: 10.1007/s10571-019-00688-2
  134. 134.Courter LA, Shaffo FC, Ghogha A, et al. BMP7-induced dendritic growth in sympathetic neurons requires p75 NTR signaling. Developmental Neurobiology. 2016;76:1003-1013
  135. 135.Guo X, Lin Y, Horbinski C, et al. Dendritic growth induced by BMP-7 requires Smad1 and proteasome activity. Journal of Neurobiology. 2001;48:120-130
  136. 136.Chandrasekaran V, Lea C, Sosa JC, et al. Reactive oxygen species are involved in BMP-induced dendritic growth in cultured rat sympathetic neurons. Molecular and Cellular Neurosciences. 2015;67:116-125
  137. 137.Vaillant AR, Zanassi P, Walsh GS, et al. Signaling mechanisms underlying reversible, activity-dependent dendrite formation. Neuron. 2002;34:985-998
  138. 138.Dedhar S, Williams B, Hannigan G. Integrin-linked kinase (ILK): A regulator of integrin and growth-factor signalling. Trends in Cell Biology. 1999;9:319-323
  139. 139.Naska S, Park KJ, Hannigan GE, et al. An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth. The Journal of Neuroscience. 2006;26:13344-13356
  140. 140.Bruckenstein DA, Higgins D. Morphological differentiation of embryonic rat sympathetic neurons in tissue culture. Developmental Biology. 1988;128:337-348
  141. 141.Stachowiak MK, Fang X, Myers JM, et al. Integrative nuclear FGFR1 signaling (INFS) as a part of a universal ?Feed-forward-and-gate? Signaling module that controls cell growth and differentiation. Journal of Cellular Biochemistry. 2003;90:662-691
  142. 142.Horbinski C, Stachowiak EK, Chandrasekaran V, et al. Bone morphogenetic protein-7 stimulates initial dendritic growth in sympathetic neurons through an intracellular fibroblast growth factor signaling pathway. Journal of Neurochemistry. 2002;80:54-63. DOI: 10.1046/j.0022-3042.2001.00657.x
  143. 143.Kim I-J, Drahushuk KM, Kim W-Y, et al. Extracellular signal-regulated kinases regulate dendritic growth in rat sympathetic neurons. The Journal of Neuroscience. 2004;24:3304-3312
  144. 144.O’Shea JJ, Gadina M, Kanno Y. Cytokine signaling: Birth of a pathway. Journal of Immunology. 2011;187:5475-5478
  145. 145.Guo X, Metzler-Northrup J, Lein P, et al. Leukemia inhibitory factor and ciliary neurotrophic factor regulate dendritic growth in cultures of rat sympathetic neurons. Brain Research Developmental Brain Research. 1997;104:101-110
  146. 146.Guo X, Chandrasekaran V, Lein P, et al. Leukemia inhibitory factor and ciliary neurotrophic factor cause dendritic retraction in cultured rat sympathetic neurons. The Journal of Neuroscience. 1999;19:2113-2121
  147. 147.Kim I-J, Beck HN, Lein PJ, et al. Interferon gamma induces retrograde dendritic retraction and inhibits synapse formation. The Journal of Neuroscience. 2002;22:4530-4539
  148. 148.Andres DA, Shi G-X, Bruun D, et al. Rit signaling contributes to interferon-γ-induced dendritic retraction via p38 mitogen-activated protein kinase activation. Journal of Neurochemistry. 2008;107:1436-1447
  149. 149.Lein PJ, Guo X, Shi GX, et al. The novel GTPase Rit differentially regulates axonal and dendritic growth. The Journal of Neuroscience. 2007;27:4725-4736
  150. 150.Higgins D, Burack M, Lein P, et al. Mechanisms of neuronal polarity. Current Opinion in Neurobiology. 1997;7:599-604
  151. 151.Konietzny A, Bär J, Mikhaylova M. Dendritic actin cytoskeleton: Structure, functions, and regulations. Frontiers in Cellular Neuroscience. 2017;11:147
  152. 152.Van Aelst L, Cline HT. Rho GTPases and activity-dependent dendrite development. Current Opinion in Neurobiology. 2004;14:297-304
  153. 153.Kim W-Y, Gonsiorek EA, Barnhart C, et al. Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation. Journal of Neurochemistry. 2009;108:1057-1071
  154. 154.Rao AN, Baas PW. Polarity Sorting of Microtubules in the Axon. Trends in Neurosciences. 2018;41:77-88. DOI: 10.1016/j.tins.2017.11.002
  155. 155.Baas PW. The role of motor proteins in establishing the microtubule arrays of axons and dendrites. Journal of Chemical Neuroanatomy. 1998;14:175-180
  156. 156.Sharp DJ, Yu W, Ferhat L, et al. Identification of a microtubule-associated motor protein essential for dendritic differentiation. The Journal of Cell Biology. 1997;138:833
  157. 157.Lin S, Liu M, Mozgova OI, et al. Mitotic motors Coregulate microtubule patterns in axons and dendrites. The Journal of Neuroscience. 2012;32:14033
  158. 158.Ferhat L, Cook C, Chauviere M, et al. Expression of the mitotic motor protein Eg5 in Postmitotic neurons: Implications for neuronal development. The Journal of Neuroscience. 1998;18:7822
  159. 159.Buster DW, Baird DH, Yu W, et al. Expression of the mitotic kinesin Kif15 in postmitotic neurons: Implications for neuronal migration and development. Journal of Neurocytology. 2003;32:79-96
  160. 160.Liu M, Nadar VC, Kozielski F, et al. Kinesin-12, a mitotic microtubule-associated motor protein, impacts axonal growth, navigation, and branching. The Journal of Neuroscience. 2010;30:14896
  161. 161.Myers KA, Baas PW. Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array. The Journal of Cell Biology. 2007;178:1081
  162. 162.Nadar VC, Ketschek A, Myers KA, et al. Kinesin-5 is essential for growth cone turning. Current Biology. 2008;18:1972
  163. 163.Kahn OI, Sharma V, González-Billault C, et al. Effects of kinesin-5 inhibition on dendritic architecture and microtubule organization. Molecular Biology of the Cell. 2015;26:66-77
  164. 164.Chandrasekaran V, Zhai Y, Wagner M, et al. Retinoic acid regulates the morphological development of sympathetic neurons. Journal of Neurobiology. 2000;42:383-393
  165. 165.Drahushuk K, Connell TD, Higgins D. Pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide inhibit dendritic growth in cultured sympathetic neurons. The Journal of Neuroscience. 2002;22:6560-6569

Written By

Vidya Chandrasekaran

Submitted: December 25th, 2021Reviewed: January 3rd, 2022Published: January 23rd, 2022