Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The sympathetic nervous system in development and disease

Abstract

The sympathetic nervous system prepares the body for ‘fight or flight’ responses and maintains homeostasis during daily activities such as exercise, eating a meal or regulation of body temperature. Sympathetic regulation of bodily functions requires the establishment and refinement of anatomically and functionally precise connections between postganglionic sympathetic neurons and peripheral organs distributed widely throughout the body. Mechanistic studies of key events in the formation of postganglionic sympathetic neurons during embryonic and early postnatal life, including axon growth, target innervation, neuron survival, and dendrite growth and synapse formation, have advanced the understanding of how neuronal development is shaped by interactions with peripheral tissues and organs. Recent progress has also been made in identifying how the cellular and molecular diversity of sympathetic neurons is established to meet the functional demands of peripheral organs. In this Review, we summarize current knowledge of signalling pathways underlying the development of the sympathetic nervous system. These findings have implications for unravelling the contribution of sympathetic dysfunction stemming, in part, from developmental perturbations to the pathophysiology of peripheral neuropathies and cardiovascular and metabolic disorders.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Organization of the mouse sympathetic nervous system and timeline of developmental events.
Fig. 2: Axon growth and innervation of peripheral targets.
Fig. 3: Axonal trafficking of survival and apoptotic signals underlie a precarious balance between neuronal survival and death.
Fig. 4: Signalling mechanisms underlying dendrite growth and synaptogenesis in sympathetic ganglia.

References

  1. Goldstein, D. S. Differential responses of components of the autonomic nervous system. Handb. Clin. Neurol. 117, 13–22 (2013).

    PubMed  Article  Google Scholar 

  2. Glebova, N. O. & Ginty, D. D. Growth and survival signals controlling sympathetic nervous system development. Annu. Rev. Neurosci. 28, 191–222 (2005).

    PubMed  Article  CAS  Google Scholar 

  3. Hasan, W. Autonomic cardiac innervation: development and adult plasticity. Organogenesis 9, 176–193 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  4. Tourtellotte, W. G. Axon transport and neuropathy: relevant perspectives on the etiopathogenesis of familial dysautonomia. Am. J. Pathol. 186, 489–499 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. Shwartz, Y. et al. Cell types promoting goosebumps form a niche to regulate hair follicle stem cells. Cell 182, 578–593.e19 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. Espinosa-Medina, I. et al. The sacral autonomic outflow is sympathetic. Science 354, 893–897 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. Borden, P., Houtz, J., Leach, S. D. & Kuruvilla, R. Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation. Cell Rep. 4, 287–301 (2013). This article provides the first evidence of a developmental role for sympathetic nerves in instructing islet morphology.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Liu, H. et al. Control of cytokinesis by beta-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment. Sci. Transl. Med. 11, eaaw6419 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Kreipke, R. E. & Birren, S. J. Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal. J. Physiol. 593, 5057–5073 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. Furlan, A. et al. Visceral motor neuron diversity delineates a cellular basis for nipple- and pilo-erection muscle control. Nat. Neurosci. 19, 1331–1340 (2016). Using single-cell sequencing, lineage and retrograde tracing, and mouse models, this elegant study identifies seven neuronal subtypes in thoracic sympathetic ganglia and reveals target-dependent mechanisms underlying neuronal diversity.

    PubMed  Article  CAS  Google Scholar 

  11. Hanani, M. & Spray, D. C. Emerging importance of satellite glia in nervous system function and dysfunction. Nat. Rev. Neurosci. 21, 485–498 (2020). This comprehensive review discusses satellite glia morphology, association with neurons and newly identified functions in neuronal activity and regeneration.

    PubMed  Article  CAS  Google Scholar 

  12. Bradke, F. & Dotti, C. G. Establishment of neuronal polarity: lessons from cultured hippocampal neurons. Curr. Opin. Neurobiol. 10, 574–581 (2000).

    PubMed  Article  CAS  Google Scholar 

  13. Rubin, E. Development of the rat superior cervical ganglion: ganglion cell maturation. J. Neurosci. 5, 673–684 (1985).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Yang, X. M. et al. Autocrine hepatocyte growth factor provides a local mechanism for promoting axonal growth. J. Neurosci. 18, 8369–8381 (1998).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. Maina, F. & Klein, R. Hepatocyte growth factor, a versatile signal for developing neurons. Nat. Neurosci. 2, 213–217 (1999).

    PubMed  Article  CAS  Google Scholar 

  16. Maina, F. et al. Multiple roles for hepatocyte growth factor in sympathetic neuron development. Neuron 20, 835–846 (1998).

    PubMed  Article  CAS  Google Scholar 

  17. Enomoto, H. et al. RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development 128, 3963–3974 (2001).

    PubMed  Article  CAS  Google Scholar 

  18. Honma, Y. et al. Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35, 267–282 (2002).

    PubMed  Article  CAS  Google Scholar 

  19. elshamy, W. M. & Ernfors, P. Requirement of neurotrophin-3 for the survival of proliferating trigeminal ganglion progenitor cells. Development 122, 2405–2414 (1996).

    PubMed  Article  CAS  Google Scholar 

  20. Kuruvilla, R. et al. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118, 243–255 (2004).

    PubMed  Article  CAS  Google Scholar 

  21. Brunet, I. et al. Netrin-1 controls sympathetic arterial innervation. J. Clin. Invest. 124, 3230–3240 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Nam, J. et al. Coronary veins determine the pattern of sympathetic innervation in the developing heart. Development 140, 1475–1485 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. Manousiouthakis, E., Mendez, M., Garner, M. C., Exertier, P. & Makita, T. Venous endothelin guides sympathetic innervation of the developing mouse heart. Nat. Commun. 5, 3918 (2014).

    PubMed  Article  CAS  Google Scholar 

  24. Wang, L. et al. A conserved axon type hierarchy governing peripheral nerve assembly. Development 141, 1875–1883 (2014).

    PubMed  Article  CAS  Google Scholar 

  25. Makita, T., Sucov, H. M., Gariepy, C. E., Yanagisawa, M. & Ginty, D. D. Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons. Nature 452, 759–763 (2008). This study reveals that sympathetic axons use prespecified routes to reach targets, suggesting the existence of molecularly distinct neuronal subtypes prior to target innervation.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Shelton, D. L. & Reichardt, L. F. Expression of the beta-nerve growth factor gene correlates with the density of sympathetic innervation in effector organs. Proc. Natl Acad. Sci. USA 81, 7951–7955 (1984).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Crowley, C. et al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 76, 1001–1011 (1994).

    PubMed  Article  CAS  Google Scholar 

  28. Glebova, N. O. & Ginty, D. D. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J. Neurosci. 24, 743–751 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. Edwards, R. H., Rutter, W. J. & Hanahan, D. Directed expression of NGF to pancreatic beta cells in transgenic mice leads to selective hyperinnervation of the islets. Cell 58, 161–170 (1989).

    PubMed  Article  CAS  Google Scholar 

  30. Hassankhani, A. et al. Overexpression of NGF within the heart of transgenic mice causes hyperinnervation, cardiac enlargement, and hyperplasia of ectopic cells. Dev. Biol. 169, 309–321 (1995).

    PubMed  Article  CAS  Google Scholar 

  31. Harrington, A. W. et al. Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146, 421–434 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Atwal, J. K., Massie, B., Miller, F. D. & Kaplan, D. R. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27, 265–277 (2000).

    PubMed  Article  CAS  Google Scholar 

  33. Spillane, M. et al. Nerve growth factor-induced formation of axonal filopodia and collateral branches involves the intra-axonal synthesis of regulators of the actin-nucleating Arp2/3 complex. J. Neurosci. 32, 17671–17689 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Bodmer, D., Ascano, M. & Kuruvilla, R. Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth. Neuron 70, 1085–1099 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. Spillane, M., Ketschek, A., Merianda, T. T., Twiss, J. L. & Gallo, G. Mitochondria coordinate sites of axon branching through localized intra-axonal protein synthesis. Cell Rep. 5, 1564–1575 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. Andreassi, C. et al. An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons. Nat. Neurosci. 13, 291–301 (2010).

    PubMed  Article  CAS  Google Scholar 

  37. Crerar, H. et al. Regulation of NGF signaling by an axonal untranslated mRNA. Neuron 102, 553–563.e8 (2019). This study provides the first evidence for a non-coding axonal mRNA in promoting sympathetic axon growth and target innervation.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. Scott-Solomon, E. & Kuruvilla, R. Prenylation of axonally translated rac1 controls NGF-dependent axon growth. Dev. Cell 53, 691–705.e7 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. Lonze, B. E., Riccio, A., Cohen, S. & Ginty, D. D. Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34, 371–385 (2002).

    PubMed  Article  CAS  Google Scholar 

  40. Eldredge, L. C. et al. Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice. Development 135, 2949–2957 (2008).

    PubMed  Article  CAS  Google Scholar 

  41. Deppmann, C. D. et al. A model for neuronal competition during development. Science 320, 369–373 (2008). Using gene expression profiling and computational modelling, this article shows that developmental competition for survival between sympathetic neurons is mediated by a series of target-initiated feedback loops.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Bodmer, D., Levine-Wilkinson, S., Richmond, A., Hirsh, S. & Kuruvilla, R. Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympathetic neurons. J. Neurosci. 29, 7569–7581 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. McWilliams, T. G., Howard, L., Wyatt, S. & Davies, A. M. Regulation of autocrine signaling in subsets of sympathetic neurons has regional effects on tissue innervation. Cell Rep. 10, 1443–1449 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Ryu, Y. K., Collins, S. E., Ho, H. Y., Zhao, H. & Kuruvilla, R. An autocrine Wnt5a-Ror signaling loop mediates sympathetic target innervation. Dev. Biol. 377, 79–89 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. Ho, H. Y. et al. Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc. Natl Acad. Sci. USA 109, 4044–4051 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  46. O’Keeffe, G. W. et al. Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation. Neural Dev. 11, 4 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. Kisiswa, L. et al. TNFα reverse signaling promotes sympathetic axon growth and target innervation. Nat. Neurosci. 16, 865–873 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. Zeng, X. et al. Innervation of thermogenic adipose tissue via a calsyntenin 3beta-S100b axis. Nature 569, 229–235 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Toma, J. S. et al. Peripheral nerve single-cell analysis identifies mesenchymal ligands that promote axonal growth. eNeuro https://doi.org/10.1523/ENEURO.0066-20.2020 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ieda, M. et al. Sema3a maintains normal heart rhythm through sympathetic innervation patterning. Nat. Med. 13, 604–612 (2007). This important study shows that aberrant sympathetic innervation during heart development results in cardiac failure in mice.

    PubMed  Article  CAS  Google Scholar 

  51. Tang, X. Q., Tanelian, D. L. & Smith, G. M. Semaphorin3A inhibits nerve growth factor-induced sprouting of nociceptive afferents in adult rat spinal cord. J. Neurosci. 24, 819–827 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. Atwal, J. K., Singh, K. K., Tessier-Lavigne, M., Miller, F. D. & Kaplan, D. R. Semaphorin 3F antagonizes neurotrophin-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase signaling: a mechanism for growth cone collapse. J. Neurosci. 23, 7602–7609 (2003).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. Gan, W. B. & Lichtman, J. W. Synaptic segregation at the developing neuromuscular junction. Science 282, 1508–1511 (1998).

    PubMed  Article  CAS  Google Scholar 

  54. Singh, K. K. et al. Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration. Nat. Neurosci. 11, 649–658 (2008). This study identifies a role for p75 in activity-dependent pruning of axon collaterals during development.

    PubMed  Article  CAS  Google Scholar 

  55. Yong, Y. et al. p75NTR and DR6 regulate distinct phases of axon degeneration demarcated by spheroid rupture. J. Neurosci. 39, 9503–9520 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. Campenot, R. B. Independent control of local environment of somas and neurites. Meth. Enzymol. 58, 302–307 (1979).

    Article  CAS  Google Scholar 

  57. Nikolaev, A., McLaughlin, T., O’Leary, D. D. & Tessier-Lavigne, M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981–989 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. Gamage, K. K. et al. Death receptor 6 promotes wallerian degeneration in peripheral axons. Curr. Biol. 27, 890–896 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. Cusack, C. L., Swahari, V., Hampton Henley, W., Michael Ramsey, J. & Deshmukh, M. Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning. Nat. Commun. 4, 1876 (2013).

    PubMed  Article  CAS  Google Scholar 

  60. Smolen, A. J. Morphology of synapses in the autonomic nervous system. J. Electron. Microsc. Tech. 10, 187–204 (1988).

    PubMed  Article  CAS  Google Scholar 

  61. Hill, C. E., Phillips, J. K. & Sandow, S. L. Development of peripheral autonomic synapses: neurotransmitter receptors, neuroeffector associations and neural influences. Clin. Exp. Pharmacol. Physiol. 26, 581–590 (1999).

    PubMed  Article  CAS  Google Scholar 

  62. Waites, C. L., Craig, A. M. & Garner, C. C. Mechanisms of vertebrate synaptogenesis. Annu. Rev. Neurosci. 28, 251–274 (2005).

    PubMed  Article  CAS  Google Scholar 

  63. Hirst, G. D., Choate, J. K., Cousins, H. M., Edwards, F. R. & Klemm, M. F. Transmission by post-ganglionic axons of the autonomic nervous system: the importance of the specialized neuroeffector junction. Neuroscience 73, 7–23 (1996).

    PubMed  Article  CAS  Google Scholar 

  64. Luther, J. A. & Birren, S. J. Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties. Auton. Neurosci. 151, 46–60 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. Lockhart, S. T., Mead, J. N., Pisano, J. M., Slonimsky, J. D. & Birren, S. J. Nerve growth factor collaborates with myocyte-derived factors to promote development of presynaptic sites in cultured sympathetic neurons. J. Neurobiol. 42, 460–476 (2000).

    PubMed  Article  CAS  Google Scholar 

  66. Yang, B., Slonimsky, J. D. & Birren, S. J. A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor. Nat. Neurosci. 5, 539–545 (2002).

    PubMed  Article  CAS  Google Scholar 

  67. Oppenheim, R. W. Cell death during development of the nervous system. Annu. Rev. Neurosci. 14, 453–501 (1991).

    PubMed  Article  CAS  Google Scholar 

  68. Oppenheim, R. W. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci. 12, 252–255 (1989).

    PubMed  Article  CAS  Google Scholar 

  69. Cowan, W. M. Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor. Annu. Rev. Neurosci. 24, 551–600 (2001).

    PubMed  Article  CAS  Google Scholar 

  70. Snider, W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638 (1994).

    PubMed  Article  Google Scholar 

  71. Smeyne, R. J. et al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 368, 246–249 (1994).

    PubMed  Article  CAS  Google Scholar 

  72. Harrington, A. W. & Ginty, D. D. Long-distance retrograde neurotrophic factor signalling in neurons. Nat. Rev. Neurosci. 14, 177–187 (2013).

    PubMed  Article  CAS  Google Scholar 

  73. Scott-Solomon, E. & Kuruvilla, R. Mechanisms of neurotrophin trafficking via Trk receptors. Mol. Cell. Neurosci. 91, 25–33 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. Delcroix, J. D. et al. NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39, 69–84 (2003).

    PubMed  Article  CAS  Google Scholar 

  75. Deinhardt, K. et al. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52, 293–305 (2006).

    PubMed  Article  CAS  Google Scholar 

  76. Ye, M., Lehigh, K. M. & Ginty, D. D. Multivesicular bodies mediate long-range retrograde NGF-TrkA signaling. eLife 7, e33012 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  77. Riccio, A., Pierchala, B., Ciarallo, C. & Ginty, D. D. An NGF-TrkA-Mediated retrograde signal to transcription factor CREB in sympathetic neurons. Science 227, 1097–1100 (1997).

    Article  Google Scholar 

  78. Suo, D. et al. Coronin-1 is a neurotrophin endosomal effector that is required for developmental competition for survival. Nat. Neurosci. 17, 36–45 (2014).

    PubMed  Article  CAS  Google Scholar 

  79. Ascano, M., Bodmer, D. & Kuruvilla, R. Endocytic trafficking of neurotrophins in neural development. Trends Cell Biol. 22, 266–273 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. Ascano, M., Richmond, A., Borden, P. & Kuruvilla, R. Axonal targeting of Trk receptors via transcytosis regulates sensitivity to neurotrophin responses. J. Neurosci. 29, 11674–11685 (2009). This study defines a positive feedback mechanism where target-derived NGF recruits TrkA receptors to axons via receptor endocytosis in cell bodies and long-distance recycling to axons.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. Yamashita, N., Joshi, R., Zhang, S., Zhang, Z. Y. & Kuruvilla, R. Phospho-regulation of soma-to-axon transcytosis of neurotrophin receptors. Dev. Cell 42, 626–639.e5 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. Pathak, A. et al. Retrograde degenerative signaling mediated by the p75 neurotrophin receptor requires p150(Glued) deacetylation by axonal HDAC1. Dev. Cell 46, 376–387.e7 (2018). This study identifies an apoptotic signalling pathway that relies on proteolytic cleavage of p75 in axons and retrograde transport of its intracellular domain.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. Escudero, C. A. et al. c-Jun N-terminal kinase (JNK)-dependent internalization and Rab5-dependent endocytic sorting mediate long-distance retrograde neuronal death induced by axonal BDNF-p75 signaling. Sci. Rep. 9, 6070 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. Mok, S. A., Lund, K. & Campenot, R. B. A retrograde apoptotic signal originating in NGF-deprived distal axons of rat sympathetic neurons in compartmented cultures. Cell Res. 19, 546–560 (2009).

    PubMed  Article  CAS  Google Scholar 

  85. Ghosh, A. S. et al. DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity. J. Cell Biol. 194, 751–764 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. Lee, R., Kermani, P., Teng, K. K. & Hempstead, B. L. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945–1948 (2001).

    PubMed  Article  CAS  Google Scholar 

  87. Nykjaer, A. et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843–848 (2004).

    PubMed  Article  CAS  Google Scholar 

  88. Voyvodic, J. T. Development and regulation of dendrites in the rat superior cervical ganglion. J. Neurosci. 7, 904–912 (1987).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. Voyvodic, J. T. Peripheral target regulation of dendritic geometry in the rat superior cervical ganglion. J. Neurosci. 9, 1997–2010 (1989).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. Andrews, T. J., Thrasivoulou, C., Nesbit, W. & Cowen, T. Target-specific differences in the dendritic morphology and neuropeptide content of neurons in the rat SCG during development and aging. J. Comp. Neurol. 368, 33–44 (1996).

    PubMed  Article  CAS  Google Scholar 

  91. Snider, W. D. Nerve growth factor enhances dendritic arborization of sympathetic ganglion cells in developing mammals. J. Neurosci. 8, 2628–2634 (1988).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. Ruit, K. G. & Snider, W. D. Administration or deprivation of nerve growth factor during development permanently alters neuronal geometry. J. Comp. Neurol. 314, 106–113 (1991).

    PubMed  Article  CAS  Google Scholar 

  93. Quach, D. H., Oliveira-Fernandes, M., Gruner, K. A. & Tourtellotte, W. G. A sympathetic neuron autonomous role for Egr3-mediated gene regulation in dendrite morphogenesis and target tissue innervation. J. Neurosci. 33, 4570–4583 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. Sharma, N. et al. Long-distance control of synapse assembly by target-derived NGF. Neuron 67, 422–434 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. Lehigh, K. M., West, K. M. & Ginty, D. D. Retrogradely transported TrkA endosomes signal locally within dendrites to maintain sympathetic neuron synapses. Cell Rep. 19, 86–100 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. Bruckenstein, D. A. & Higgins, D. Morphological differentiation of embryonic rat sympathetic neurons in tissue culture. I. Conditions under which neurons form axons but not dendrites. Dev. Biol. 128, 324–336 (1988).

    PubMed  Article  CAS  Google Scholar 

  97. Vaillant, A. R. et al. Signaling mechanisms underlying reversible, activity-dependent dendrite formation. Neuron 34, 985–998 (2002).

    PubMed  Article  CAS  Google Scholar 

  98. Rubin, E. Development of the rat superior cervical ganglion: ingrowth of preganglionic axons. J. Neurosci. 5, 685–696 (1985).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. Naska, S. et al. An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth. J. Neurosci. 26, 13344–13356 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. Chong, Y. et al. Removing 4E-BP enables synapses to refine without postsynaptic activity. Cell Rep. 23, 11–22 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. Lein, P., Johnson, M., Guo, X., Rueger, D. & Higgins, D. Osteogenic protein-1 induces dendritic growth in rat sympathetic neurons. Neuron 15, 597–605 (1995).

    PubMed  Article  CAS  Google Scholar 

  102. Majdazari, A. et al. Dendrite complexity of sympathetic neurons is controlled during postnatal development by BMP signaling. J. Neurosci. 33, 15132–15144 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. Beck, H. N., Drahushuk, K., Jacoby, D. B., Higgins, D. & Lein, P. J. Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons. BMC Neurosci. 2, 12 (2001).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. Lein, P. J. et al. Glia induce dendritic growth in cultured sympathetic neurons by modulating the balance between bone morphogenetic proteins (BMPs) and BMP antagonists. J. Neurosci. 22, 10377–10387 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. Tropea, M., Johnson, M. I. & Higgins, D. Glial cells promote dendritic development in rat sympathetic neurons in vitro. Glia 1, 380–392 (1988).

    PubMed  Article  CAS  Google Scholar 

  106. Pravoverov, K. et al. MicroRNAs are necessary for BMP-7-induced dendritic growth in cultured rat sympathetic neurons. Cell Mol. Neurobiol. 39, 917–934 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. Courter, L. A. et al. BMP7-induced dendritic growth in sympathetic neurons requires p75(NTR) signaling. Dev. Neurobiol. 76, 1003–1013 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. Rubin, E. Development of the rat superior cervical ganglion: initial stages of synapse formation. J. Neurosci. 5, 697–704 (1985).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  109. Devay, P., McGehee, D. S., Yu, C. R. & Role, L. W. Target-specific control of nicotinic receptor expression at developing interneuronal synapses in chick. Nat. Neurosci. 2, 528–534 (1999).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. Rosenberg, M. M., Blitzblau, R. C., Olsen, D. P. & Jacob, M. H. Regulatory mechanisms that govern nicotinic synapse formation in neurons. J. Neurobiol. 53, 542–555 (2002).

    PubMed  Article  CAS  Google Scholar 

  111. Purves, D. & Nja, A. Effect of nerve growth factor on synaptic depression after axotomy. Nature 260, 535–536 (1976).

    PubMed  Article  CAS  Google Scholar 

  112. Nja, A. & Purves, D. The effects of nerve growth factor and its antiserum on synapses in the superior cervical ganglion of the guinea-pig. J. Physiol. 277, 53–75 (1978).

    PubMed  Article  CAS  Google Scholar 

  113. Causing, C. G. et al. Synaptic innervation density is regulated by neuron-derived BDNF. Neuron 18, 257–267 (1997).

    PubMed  Article  CAS  Google Scholar 

  114. Gingras, J., Rassadi, S., Cooper, E. & Ferns, M. Agrin plays an organizing role in the formation of sympathetic synapses. J. Cell Biol. 158, 1109–1118 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. Conroy, W. G., Liu, Z., Nai, Q., Coggan, J. S. & Berg, D. K. PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons. Neuron 38, 759–771 (2003).

    PubMed  Article  CAS  Google Scholar 

  116. Purves, D. & Lichtman, J. W. Elimination of synapses in the developing nervous system. Science 210, 153–157 (1980).

    PubMed  Article  CAS  Google Scholar 

  117. Lichtman, J. W. & Purves, D. The elimination of redundant preganglionic innervation to hamster sympathetic ganglion cells in early post-natal life. J. Physiol. 301, 213–228 (1980).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. Sanes, J. R. & Lichtman, J. W. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat. Rev. Neurosci. 2, 791–805 (2001).

    PubMed  Article  CAS  Google Scholar 

  119. Krishnaswamy, A. & Cooper, E. An activity-dependent retrograde signal induces the expression of the high-affinity choline transporter in cholinergic neurons. Neuron 61, 272–286 (2009). This study provides rare insight into synapse maintenance in sympathetic ganglia by showing that synapses remain structurally intact without synaptic activity, although high-frequency transmission is impaired in α3 nAChR-knockout mice.

    PubMed  Article  CAS  Google Scholar 

  120. Jobling, P. & Gibbins, I. L. Electrophysiological and morphological diversity of mouse sympathetic neurons. J. Neurophysiol. 82, 2747–2764 (1999).

    PubMed  Article  CAS  Google Scholar 

  121. Ernsberger, U., Deller, T. & Rohrer, H. The diversity of neuronal phenotypes in rodent and human autonomic ganglia. Cell Tissue Res. 382, 201–231 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  122. Cane, K. N. & Anderson, C. R. Generating diversity: mechanisms regulating the differentiation of autonomic neuron phenotypes. Auton. Neurosci. 151, 17–29 (2009).

    PubMed  Article  CAS  Google Scholar 

  123. Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. Furlan, A., Lubke, M., Adameyko, I., Lallemend, F. & Ernfors, P. The transcription factor Hmx1 and growth factor receptor activities control sympathetic neurons diversification. EMBO J. 32, 1613–1625 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. Zhang, Q. et al. Temporal requirements for ISL1 in sympathetic neuron proliferation, differentiation, and diversification. Cell Death Dis. 9, 247 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. Guidry, G. & Landis, S. C. Target-dependent development of the vesicular acetylcholine transporter in rodent sweat gland innervation. Dev. Biol. 199, 175–184 (1998).

    PubMed  Article  CAS  Google Scholar 

  127. Ernsberger, U. & Rohrer, H. Development of the cholinergic neurotransmitter phenotype in postganglionic sympathetic neurons. Cell Tissue Res. 297, 339–361 (1999).

    PubMed  Article  CAS  Google Scholar 

  128. Asmus, S. E., Parsons, S. & Landis, S. C. Developmental changes in the transmitter properties of sympathetic neurons that innervate the periosteum. J. Neurosci. 20, 1495–1504 (2000).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. Francis, N. J. & Landis, S. C. Cellular and molecular determinants of sympathetic neuron development. Annu. Rev. Neurosci. 22, 541–566 (1999).

    PubMed  Article  CAS  Google Scholar 

  130. Schotzinger, R. J. & Landis, S. C. Acquisition of cholinergic and peptidergic properties by sympathetic innervation of rat sweat glands requires interaction with normal target. Neuron 5, 91–100 (1990).

    PubMed  Article  CAS  Google Scholar 

  131. Habecker, B. A. & Landis, S. C. Noradrenergic regulation of cholinergic differentiation. Science 264, 1602–1604 (1994).

    PubMed  Article  CAS  Google Scholar 

  132. Saadat, S., Sendtner, M. & Rohrer, H. Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture. J. Cell Biol. 108, 1807–1816 (1989).

    PubMed  Article  CAS  Google Scholar 

  133. Yamamori, T. et al. The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science 246, 1412–1416 (1989).

    PubMed  Article  CAS  Google Scholar 

  134. Bamber, B. A., Masters, B. A., Hoyle, G. W., Brinster, R. L. & Palmiter, R. D. Leukemia inhibitory factor induces neurotransmitter switching in transgenic mice. Proc. Natl Acad. Sci. USA 91, 7839–7843 (1994).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. Rao, M. S. et al. Leukemia inhibitory factor mediates an injury response but not a target-directed developmental transmitter switch in sympathetic neurons. Neuron 11, 1175–1185 (1993).

    PubMed  Article  CAS  Google Scholar 

  136. Masu, Y. et al. Disruption of the CNTF gene results in motor neuron degeneration. Nature 365, 27–32 (1993).

    PubMed  Article  CAS  Google Scholar 

  137. Francis, N. J., Asmus, S. E. & Landis, S. C. CNTF and LIF are not required for the target-directed acquisition of cholinergic and peptidergic properties by sympathetic neurons in vivo. Dev. Biol. 182, 76–87 (1997).

    PubMed  Article  CAS  Google Scholar 

  138. Ootsuka, Y. & Blessing, W. W. Inhibition of medullary raphe/parapyramidal neurons prevents cutaneous vasoconstriction elicited by alerting stimuli and by cold exposure in conscious rabbits. Brain Res. 1051, 189–193 (2005).

    PubMed  Article  CAS  Google Scholar 

  139. Benedek, M. & Kaernbach, C. Physiological correlates and emotional specificity of human piloerection. Biol. Psychol. 86, 320–329 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  140. Dart, A. M., Du, X. J. & Kingwell, B. A. Gender, sex hormones and autonomic nervous control of the cardiovascular system. Cardiovasc. Res. 53, 678–687 (2002).

    PubMed  Article  CAS  Google Scholar 

  141. Hinojosa-Laborde, C., Chapa, I., Lange, D. & Haywood, J. R. Gender differences in sympathetic nervous system regulation. Clin. Exp. Pharmacol. Physiol. 26, 122–126 (1999).

    PubMed  Article  CAS  Google Scholar 

  142. Jessen, K. R. & Mirsky, R. The origin and development of glial cells in peripheral nerves. Nat. Rev. Neurosci. 6, 671–682 (2005).

    PubMed  Article  CAS  Google Scholar 

  143. Monk, K. R., Feltri, M. L. & Taveggia, C. New insights on Schwann cell development. Glia 63, 1376–1393 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  144. Pannese, E. The satellite cells of the sensory ganglia. Adv. Anat. Embryol. Cell Biol. 65, 1–111 (1981).

    PubMed  Article  CAS  Google Scholar 

  145. Hanani, M. Satellite glial cells in sympathetic and parasympathetic ganglia: in search of function. Brain Res. Rev. 64, 304–327 (2010).

    PubMed  Article  CAS  Google Scholar 

  146. Paratore, C., Goerich, D. E., Suter, U., Wegner, M. & Sommer, L. Survival and glial fate acquisition of neural crest cells are regulated by an interplay between the transcription factor Sox10 and extrinsic combinatorial signaling. Development 128, 3949–3961 (2001).

    PubMed  Article  CAS  Google Scholar 

  147. Britsch, S. et al. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 15, 66–78 (2001).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. Hall, A. K. & Landis, S. C. Early commitment of precursor cells from the rat superior cervical ganglion to neuronal or nonneuronal fates. Neuron 6, 741–752 (1991).

    PubMed  Article  CAS  Google Scholar 

  149. Kurtz, A. et al. The expression pattern of a novel gene encoding brain-fatty acid binding protein correlates with neuronal and glial cell development. Development 120, 2637–2649 (1994).

    PubMed  Article  CAS  Google Scholar 

  150. Shi, H. et al. Nestin expression defines both glial and neuronal progenitors in postnatal sympathetic ganglia. J. Comp. Neurol. 508, 867–878 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Hall, A. K. & Landis, S. C. Division and migration of satellite glia in the embryonic rat superior cervical ganglion. J. Neurocytol. 21, 635–647 (1992).

    PubMed  Article  CAS  Google Scholar 

  152. Fagan, A. M. et al. TrkA, but not TrkC, receptors are essential for survival of sympathetic neurons in vivo. J. Neurosci. 16, 6208–6218 (1996).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. Freeman, M. R. Drosophila central nervous system glia. Cold Spring Harb. Perspect. Biol. 7, a020552 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  154. Oikonomou, G. & Shaham, S. The glia of Caenorhabditis elegans. Glia 59, 1253–1263 (2011).

    PubMed  Article  Google Scholar 

  155. Enes, J. et al. Satellite glial cells modulate cholinergic transmission between sympathetic neurons. PLoS One 15, e0218643 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. McFarlane, S. & Cooper, E. Extrinsic factors influence the expression of voltage-gated K currents on neonatal rat sympathetic neurons. J. Neurosci. 13, 2591–2600 (1993).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. Wu, H. H. et al. Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat. Neurosci. 12, 1534–1541 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  158. Low, P. A. Autonomic neuropathies. Curr. Opin. Neurol. 15, 605–609 (2002).

    PubMed  Article  Google Scholar 

  159. Goldstein, D. S., Robertson, D., Esler, M., Straus, S. E. & Eisenhofer, G. Dysautonomias: clinical disorders of the autonomic nervous system. Ann. Intern. Med. 137, 753–763 (2002).

    PubMed  Article  Google Scholar 

  160. Saravia, F. & Homo-Delarche, F. Is innervation an early target in autoimmune diabetes? Trends Immunol. 24, 574–579 (2003).

    PubMed  Article  CAS  Google Scholar 

  161. Hanoun, M., Maryanovich, M., Arnal-Estape, A. & Frenette, P. S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360–373 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  162. Axelrod, F. B., Nachtigal, R. & Dancis, J. Familial dysautonomia: diagnosis, pathogenesis and management. Adv. Pediatr. 21, 75–96 (1974).

    PubMed  CAS  Google Scholar 

  163. Li, L., Gruner, K. & Tourtellotte, W. G. Retrograde nerve growth factor signaling abnormalities in familial dysautonomia. J. Clin. Invest. 130, 2478–2487 (2020). Using a combination of mouse models and compartmentalized neuron cultures, this elegant study reveals aberrant TrkA phosphorylation during retrograde transport as the basis for neuronal loss in an autonomic neuropathy.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. Patel, A. et al. RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome. Nat. Commun. 6, 10119 (2015).

    PubMed  Article  CAS  Google Scholar 

  165. Ieda, M. Heart development, diseases, and regeneration- new approaches from innervation, fibroblasts, and reprogramming. Circ. J. 80, 2081–2088 (2016).

    PubMed  Article  CAS  Google Scholar 

  166. Lefcort, F., Mergy, M., Ohlen, S. B., Ueki, Y. & George, L. Animal and cellular models of familial dysautonomia. Clin. Auton. Res. 27, 235–243 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  167. Jackson, M. Z., Gruner, K. A., Qin, C. & Tourtellotte, W. G. A neuron autonomous role for the familial dysautonomia gene ELP1 in sympathetic and sensory target tissue innervation. Development 141, 2452–2461 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  168. O’Driscoll, D. M. et al. Cardiac and sympathetic activation are reduced in children with Down syndrome and sleep disordered breathing. Sleep 35, 1269–1275 (2012).

    PubMed  PubMed Central  Google Scholar 

  169. Yiallourou, S. R., Witcombe, N. B., Sands, S. A., Walker, A. M. & Horne, R. S. The development of autonomic cardiovascular control is altered by preterm birth. Early Hum. Dev. 89, 145–152 (2013).

    PubMed  Article  Google Scholar 

  170. Crump, C., Winkleby, M. A., Sundquist, K. & Sundquist, J. Risk of hypertension among young adults who were born preterm: a Swedish national study of 636,000 births. Am. J. Epidemiol. 173, 797–803 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  171. Tucker, D. C. & Johnson, A. K. Development of autonomic control of heart rate in genetically hypertensive and normotensive rats. Am. J. Physiol. 246, R570–R577 (1984).

    PubMed  CAS  Google Scholar 

  172. Ieda, M. et al. Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. J. Clin. Invest. 113, 876–884 (2004).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. Cao, J. M. et al. Nerve sprouting and sudden cardiac death. Circ. Res. 86, 816–821 (2000).

    PubMed  Article  CAS  Google Scholar 

  174. Xie, A. X., Lee, J. J. & McCarthy, K. D. Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo. JCI Insight 2, e90565 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  175. Lin, E. E., Scott-Solomon, E. & Kuruvilla, R. Peripheral innervation in the regulation of glucose homeostasis. Trends Neurosci. 44, 189–202 (2021).

    PubMed  Article  CAS  Google Scholar 

  176. Mei, Q., Mundinger, T. O., Lernmark, A. & Taborsky, G. J. Jr Early, selective, and marked loss of sympathetic nerves from the islets of BioBreeder diabetic rats. Diabetes 51, 2997–3002 (2002).

    PubMed  Article  CAS  Google Scholar 

  177. Persson-Sjogren, S., Holmberg, D. & Forsgren, S. Remodeling of the innervation of pancreatic islets accompanies insulitis preceding onset of diabetes in the NOD mouse. J. Neuroimmunol. 158, 128–137 (2005).

    PubMed  Article  CAS  Google Scholar 

  178. Campanucci, V., Krishnaswamy, A. & Cooper, E. Diabetes depresses synaptic transmission in sympathetic ganglia by inactivating nAChRs through a conserved intracellular cysteine residue. Neuron 66, 827–834 (2010).

    PubMed  Article  CAS  Google Scholar 

  179. Schreiber, R., Levy, J., Loewenthal, N., Pinsk, V. & Hershkovitz, E. Decreased first phase insulin response in children with congenital insensitivity to pain with anhidrosis. J. Pediatr. Endocrinol. Metab. 18, 873–877 (2005).

    PubMed  Article  CAS  Google Scholar 

  180. Indo, Y. et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat. Genet. 13, 485–488 (1996).

    PubMed  Article  CAS  Google Scholar 

  181. Lomax, A. E., Sharkey, K. A. & Furness, J. B. The participation of the sympathetic innervation of the gastrointestinal tract in disease states. Neurogastroenterol. Motil. 22, 7–18 (2010).

    PubMed  CAS  Google Scholar 

  182. Gabanyi, I. et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  183. Muller, P. A. et al. Microbiota modulate sympathetic neurons via a gut-brain circuit. Nature 583, 441–446 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  184. Zahalka, A. H. & Frenette, P. S. Nerves in cancer. Nat. Rev. Cancer 20, 143–157 (2020). This timely review covers emerging evidence for contributions of sympathetic nerves to tumour growth and discusses nerve manipulation as a novel therapeutic opportunity in cancer.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. Peruzzi, D., Hendley, E. D. & Forehand, C. J. Hypertrophy of stellate ganglion cells in hypertensive, but not hyperactive, rats. Am. J. Physiol. 261, R979–R984 (1991).

    PubMed  CAS  Google Scholar 

  186. Avraham, O. et al. Satellite glial cells promote regenerative growth in sensory neurons. Nat. Commun. 11, 4891 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. Oh, Y. et al. Functional coupling with cardiac muscle promotes maturation of hPSC-derived sympathetic neurons. Cell Stem Cell 19, 95–106 (2016). This study describes the derivation of functional sympathetic neurons from human pluripotent stem cells, facilitating the study of human sympathetic neuron development in normal and disease conditions.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  188. Zeltner, N. et al. Capturing the biology of disease severity in a PSC-based model of familial dysautonomia. Nat. Med. 22, 1421–1427 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  189. Markus, A., Patel, T. D. & Snider, W. D. Neurotrophic factors and axonal growth. Curr. Opin. Neurobiol. 12, 523–531 (2002).

    PubMed  Article  CAS  Google Scholar 

  190. Gallo, G. & Letourneau, P. C. Localized sources of neurotrophins initiate axon collateral sprouting. J. Neurosci. 18, 5403–5414 (1998).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  191. Kawasaki, T. et al. Requirement of neuropilin 1-mediated Sema3A signals in patterning of the sympathetic nervous system. Development 129, 671–680 (2002).

    PubMed  Article  CAS  Google Scholar 

  192. Maden, C. H. et al. NRP1 and NRP2 cooperate to regulate gangliogenesis, axon guidance and target innervation in the sympathetic nervous system. Dev. Biol. 369, 277–285 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  193. Schafer, T., Schwab, M. E. & Thoenen, H. Increased formation of preganglionic synapses and axons due to a retrograde trans-synaptic action of nerve growth factor in the rat sympathetic nervous system. J. Neurosci. 3, 1501–1510 (1983).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  194. Tasdemir-Yilmaz, O. E. et al. Diversity of developing peripheral glia revealed by single-cell RNA sequencing. Dev Cell. 56, P2516–2535.E8 (2021).

    Article  CAS  Google Scholar 

  195. Kuruvilla, R., Ye, H. & Ginty, D. D. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 27, 499–512 (2000).

    PubMed  Article  CAS  Google Scholar 

  196. Riccio, A., Ahn, S., Davenport, C. M., Blendy, J. & Ginty, D. D. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286, 2358–2361 (1999).

    PubMed  Article  CAS  Google Scholar 

  197. Chan, W. H., Anderson, C. R. & Gonsalvez, D. G. From proliferation to target innervation: signaling molecules that direct sympathetic nervous system development. Cell Tissue Res. 372, 171–193 (2018).

    PubMed  Article  CAS  Google Scholar 

  198. Ma, Q., Kintner, C. & Anderson, D. J. Identification of neurogenin, a vertebrate neuronal determination gene. Cell 87, 43–52 (1996).

    PubMed  Article  CAS  Google Scholar 

  199. Perez, S. E., Rebelo, S. & Anderson, D. J. Early specification of sensory neuron fate revealed by expression and function of neurogenins in the chick embryo. Development 126, 1715–1728 (1999).

    PubMed  Article  CAS  Google Scholar 

  200. Gonsalvez, D. G. et al. Proliferation and cell cycle dynamics in the developing stellate ganglion. J. Neurosci. 33, 5969–5979 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. Goridis, C. & Rohrer, H. Specification of catecholaminergic and serotonergic neurons. Nat. Rev. Neurosci. 3, 531–541 (2002).

    PubMed  Article  CAS  Google Scholar 

  202. Rothman, T. P., Gershon, M. D. & Holtzer, H. The relationship of cell division to the acquisition of adrenergic characteristics by developing sympathetic ganglion cell precursors. Dev. Biol. 65, 322–341 (1978).

    PubMed  Article  CAS  Google Scholar 

  203. DiCicco-Bloom, E., Townes-Anderson, E. & Black, I. B. Neuroblast mitosis in dissociated culture: regulation and relationship to differentiation. J. Cell Biol. 110, 2073–2086 (1990).

    PubMed  Article  CAS  Google Scholar 

  204. Armstrong, A., Ryu, Y. K., Chieco, D. & Kuruvilla, R. Frizzled3 is required for neurogenesis and target innervation during sympathetic nervous system development. J. Neurosci. 31, 2371–2381 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  205. Andres, R. et al. Multiple effects of artemin on sympathetic neurone generation, survival and growth. Development 128, 3685–3695 (2001).

    PubMed  Article  CAS  Google Scholar 

  206. Zackenfels, K., Oppenheim, R. W. & Rohrer, H. Evidence for an important role of IGF-I and IGF-II for the early development of chick sympathetic neurons. Neuron 14, 731–741 (1995).

    PubMed  Article  CAS  Google Scholar 

  207. Hildreth, V., Anderson, R. H. & Henderson, D. J. Autonomic innervation of the developing heart: origins and function. Clin. Anat. 22, 36–46 (2009).

    PubMed  Article  Google Scholar 

  208. Kugler, J. D. et al. Effect of chemical sympathectomy on myocardial cell division in the newborn rat. Pediatr. Res. 14, 881–884 (1980).

    PubMed  Article  CAS  Google Scholar 

  209. Ogawa, S. et al. Direct contact between sympathetic neurons and rat cardiac myocytes in vitro increases expression of functional calcium channels. J. Clin. Invest. 89, 1085–1093 (1992).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  210. Triposkiadis, F. et al. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J. Am. Coll. Cardiol. 54, 1747–1762 (2009).

    PubMed  Article  CAS  Google Scholar 

  211. Woods, S. C. & Porte, D. Jr Neural control of the endocrine pancreas. Physiol. Rev. 54, 596–619 (1974).

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Haiqing Zhao, Chris Deppmann, Raluca Pascalau and all members of the Kuruvilla laboratory for helpful comments. We apologize to authors whose work could not be cited due to space limitations. The authors’ work is supported by NIH R01 awards (NS114478 and NS107342) to R. Kuruvilla.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to the preparation of this manuscript

Corresponding author

Correspondence to Rejji Kuruvilla.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neuroscience thanks W. Tourtellotte, Y. Sun, and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Scott-Solomon, E., Boehm, E. & Kuruvilla, R. The sympathetic nervous system in development and disease. Nat Rev Neurosci 22, 685–702 (2021). https://doi.org/10.1038/s41583-021-00523-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-021-00523-y

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing