SIGNALING PATHWAYS IN THE CONTROL OF EMBRYONIC DEVELOPMENT OF THE ENTERIC NERVOUS SYSTEM

  • Milos Djuknic University of Belgrade, Faculty of Medicine, Republic of Serbia
  • Nela Puskas University of Belgrade, Faculty of Medicine, Institute of Histology and Embryology „Prof. dr Aleksandar Dj. Kostic“, Belgrade, Serbia
  • Milica Labudovic Borovic University of Belgrade, Faculty of Medicine, Institute of Histology and Embryology „Prof. dr Aleksandar Dj. Kostic“, Belgrade, Republic of Serbia
  • Radmila Jankovic University of Belgrade, Faculty of Medicine, Institute of Pathology „Prof. dr Djordje Joannovic“, Belgrade, Republic of Serbia
Keywords: enterički nervni sistem, embrionalni razvoj, signalni putevi, Hiršprungova bolest

Abstract


The enteric nervous system (ENS) provides intrinsic innervation of the gastrointestinal tract and is the largest and most complex part of the peripheral nervous system. Its functions are vital for life and include control of motility of the digestive tract, secretion, as well as fluid and electrolyte exchange through the intestinal mucosa. ENS is capable of performing most of these functions completely autonomously. A large number of developmental and genetic studies of the most common congenital disease of the ENS, Hischsprung' s disease, has made a major contribution to the understanding of the embryonic development of the ENS. ENS cells raise from the vagal (mostly) and sacral region of the neural crest. These precursor cells migrate along the primitive gut in opposite directions, in order to colonize the entire gut. Proliferation, migration, neuro-glial differentiation, and other processes through which precursor cells of the ENS undergo, are regulated by various signaling pathways. Some of the most important molecules that participate in the regulation of the proper development of the ENS are GDNF (Glial Derived Neurotrophic Fatcor) and its receptor RET (REarranged during Transfection), endothelin 3 and its receptor EDNRB (endothelin receptor type B), transcription factors SOX10 (SRY-box transcription factor 10), PHOX2B (Paired-like Homeobox 2B), morphogens such as BMP 2 and 4 (Bone Morphogenic Proteins) and others. Although our knowledge about control of the development of the ENS has increased significantly in recent years, complexity of structure and function of the ENS requires further research. This review summarizes our current understanding of the most important regulatory mechanisms and signaling pathways involved in the development of the ENS.

References

1. Yntema CL, Hammond WS. The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J Comp Neurol 1954; 101(2):515-41. doi: 10.1002/cne.901010212.

2. Burns AJ, Douarin NM. The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. Development 1998; 125(21):4335-47. doi: 10.1242/dev.125.21.4335.

3. Allan IJ, Newgreen DF. The origin and differentiation of enteric neurons of the intestine of the fowl embryo. Am J Anat 1980; 157(2):137-54. doi: 10.1002/aja.1001570203.

4. Hansen MB. The enteric nervous system I: organisation and calssification. Pharmacol Toxicol 2003; 92(3):105-13. doi: 10.1034/j.1600-0773.2003.t01-1-920301.x.

5. Druckenbrod NR, Epstein ML. The pattern of neural crest advance in the cecum and colon. Dev Biol 2005; 287(1):125-33. doi: 10.1016/j.ydbio.2005.08.040.

6. Đuknić M, Puškaš N, Labudović Borović M, Janković R. Poreklo ćelija enteričkog nervnog sistema i putevi migracije tokom embrionalnog razvoja. Zdravstvena zaštita 2022; 51(2):20-35. doi: 10.5937/zdravzast51-37799.

7. Obermayr F, Hotta R, Enomoto H, Young HM. Development and developmental disorders of the enteric nervous system. Nat Rev Gastroenterol Hepatol 2013; 10(1):43-57. doi: 10.1038/nrgastro.2012.234.

8. Janković R. Modern diagnostics of Hirschsprung disease and related disorders. Materia medica 2016; 32(2):1478-82.

9. Janković R. Analiza glija indeksa i Kahalovih ćelija u biopsijama debelog creva dece sa Hiršprungovom bolešću i srodnim oboljenjima [disertacija]. Beograd: Medicinski fakultet Univerziteta u Beogradu; 2016.

10. Jankovic R, Sindjic-Antunovic S, Lukac M, Vujovic D, Jevtic J, Skender-Gazibara M. Altered Distribution of Interstitial Cells of Cajal in Normoganglionic and Transitional Zone of Hirschsprung Disease and Their Clinical Significance. Central Eur J Paed 2020; 16(1):1-9. doi: 10.5457/p2005-114.251.

11. Rao M, Gershon MD. Enteric nervous system development: what could possibly go wrong? Nat Rev Neurosci 2018; 19(9):552-65. doi: 10.1038/s41583-018-0041-0.

12. Goldstein AM, Hofstra RM, Burns AJ. Building a brain in the gut: development of the enteric nervous system. Clin Genet 2013; 83(4):307-16. doi: 10.1111/cge.12054.

13. Nagy N, Goldstein AM. Enteric nervous system development: A crest cell’s journey from neural tube to colon. Semin Cell Dev Biol 2017; 66:94-106. doi: 10.1016/j.semcdb.2017.01.006.

14. Simkin JE, Zhang D, Rollo BN, Newgreen DF. Retinoic acid upregulates ret and induces chain migration and population expansion in vagal neural crest cells to colonize the embryonic gut. PLoS One 2013; 8(5):e64077. doi: 10.1371/journal.pone.0064077.

15. Gao T, Wright-Jin EC, Sengupta R, Anderson JB, Heuckeroth RO. Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system. JCI Insight 2021; 6(10):e145854. doi: 10.1172/jci.insight.145854. 

16. Kawai K, Takahashi M. Intracellular RET signaling pathways activated by GDNF. Cell Tissue Res 2020; 382(1) :113-123. doi: 10.1007/s00441-020-03262-1.

17. Mwizerwa O, Das P, Nagy N, Akbareian SE, Mably JD, Goldstein AM. Gdnf is mitogenic, neurotrophic, and chemoattractive to enteric neural crest cells in the embryonic colon. Dev Dyn 2011; 240(6): 1402-11. doi: 10.1002/dvdy.22630. 

18. Hearn CJ, Murphy M, Newgreen D. GDNF and ET-3 differentially modulate the numbers of avian enteric neural crest cells and enteric neurons in vitro. Dev Biol 1998; 197(1):93-105. doi: 10.1006/dbio.1998.8876.

19. Anderson RB, Bergner AJ, Taniguchi M, Fujisawa H, Forrai A, Robb L et al. Effects of different regions of the developing gut on the migration of enteric neural crest-derived cells: a role for Sema3A, but not Sema3F. Dev Biol 2007; 305(1):287-99. doi: 10.1016/j.ydbio.2007.02.020.

20. Diposarosa R, Bustam NA, Sahiratmadja E, Susanto PS, Sribudiani Y. Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung’s disease. Heliyon 2021; 7(6):e07308. doi: 10.1016/j.heliyon.2021.e07308.

21. Amiel J, Lyonnet S. Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet 2001; 38(11):729-39.  doi: 10.1136/jmg.38.11.729.

22. Uesaka T, Nagashimada M, Yonemura S, Enomoto H. Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice. J Clin Invest 2008; 118(5):1890-8. doi: 10.1172/JCI34425. 

23. Nagy N, Guyer RA, Hotta R, Zhang D, Newgreen DF, Halasy V et al. RET overactivation leds to concurrent Hirschsprung disease and intestinal ganglioneuromas. Development 2020; 147(21):dev190900. doi: 10.1242/dev.190900. 

24. Soret R, Schneider S, Bernas G, Christophers B, Souchkova O, Charrier B et al. Glial Cell-Derived Neurotrophic Factor Induces Enteric Neurogenesis and Improve Colon Structure and Function in Mouse Models of Hirschsprung Disease. Gastroenterology 2020; 159(5):1824-38. e17. doi: 10.1053/j.gastro.2020.07.018.

25. Watanabe Y, Stanchina L, Lecerf L, Gacem N, Conidi A, Baral V et al. Differentiation of Mouse Enteric Nervous System Progenitor Cells Is Controlled by Endothelin 3 and Requires Regulation of Ednrb by SOX10 and ZEB2. Gastroenterology 2017; 152(5):1139-50. doi: 10.1053/j.gastro.2016.12.034.

26. Nagy N, Goldstein AM. Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system. Dev Biol 2006; 293(1):203-17. doi: 10.1016/j.ydbio.2006.01.032.

27. Barlow A, de Graaff E, Pachnis V. Enteric nervous system progenitors are coordinately controlled by the G protein-coupled receptor EDNRB and the receptor tyrosine kinase RET. Neuron 2003; 40(5):905-16. doi: 10.1016/s0896-6273(03)00730-x.

28. Read AP, Newton VE. Waardenburg syndrome. J Med Genet 1997; 34(8):656-65. doi: 10.1136/jmg.34.8.656.

29. Okamura Y, Saga Y. Notch signaling is required for the maintenance of enteric neural crest progenitors. Development 2008; 135(21):3555-65. doi: 10.1242/dev.022319.

30. Taylor MK, Yeager K, Morrison SJ. Physiological Notch signaling promotes gliogenesis in the developing peripheral and central nervous systems. Development 2007; 134(13):2435-47. doi: 10.1242/dev.005520. 

31. Pawolski W, Schmidt MHH. Neuron-Glia Interaction in the Developing and Adult Enteric Nervous System. Cells 2021; 10(1): 47. doi: 10.3390/cells10010047.

32. Liu JA, Ngan ES. Hedgehog and Notch signaling in enteric nervous system development. Neurosignals 2014; 22(1):1-13. doi: 10.1159/000356305.

33. Chalazonitis A, Kessler JA. Pleiotropic effects of the bone morphogenetic proteins on development of the enteric nervous system. Dev Neurobiol 2012; 72(6):843-56. doi: 10.1002/dneu.22002. 

34. Anitha M, Shahnavaz N, Qayed E, Joseph I, Gossrau G, Mwangi S et al. BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway. Am J Physiol Gastrointest Liver Physiol 2010; 298(3):G375-83.  doi: 10.1152/ajpgi.00343.2009.

35. Chalazonitis A, D'Autréaux F, Pham TD, Kessler JA, Gershon MD. Bone morphogenetic proteins regulate enteric gliogenesis by modulating ErbB3 signaling. Dev Biol 2011; 350(1):64-79. doi: 10.1016/j.ydbio.2010.11.017.

36. Goldstein AM, Brewer KC, Doyle AM, Nagy N, Roberts DJ. BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system. Mech Dev 2005; 122(6):821-33.  doi: 10.1016/j.mod.2005.03.003. 

37. Gonzales J, Le Berre-Scoul C, Dariel A, Bréhéret P, Neunlist M, Boudin H. Semaphorin 3A controls enteric neuron connectivity and is inversely associated with synapsin 1 expression in Hirschsprung disease. Sci Rep 2020; 10(1):15119. doi: 10.1038/s41598-020-71865-3. 

38. Wang LL, Zhang Y, Fan Y, Li H, Zhou FH, Miao JN, et al. SEMA3A rs7804122 polymorphism is associated with Hirschsprung disease in the Northeastern region of China. Birth Defects Res A Clin Mol Teratol 2012; 94(2):91-5. doi: 10.1002/bdra.22866. 

39. Anderson RB, Turner KN, Nikonenko AG, Hemperly J, Schachner M, Young HM. The cell adhesion molecule L1 is required for chain migration of neural crest cells in the developingmouse gut. Gastroenterology 2006; 130:1221–32. doi:10.1053/j.gastro.2006.01.002.

40. Broders-Bondon F, Paul-Gilloteaux P, Carlier C, Radice GL, Dufour S. N-cadherin and β1-integrins cooperate during the development of the enteric nervous system. Dev Biol 2012; 364:178–91. doi: 10.1016/j.ydbio.2012.02.001.

41. Wallace AS, Schmidt C, Schachner M, Wegner M, Anderson RB. L1cam acts as a modifier gene during enteric nervous system development. Neurobiol Dis 2012; 40:622–33. doi: 10.1016/j.nbd.2010.08.006.

 

 

Published
2022/10/09
Section
Review article