Abstract
Enteric neurons arise from vagal and sacral level neural crest cells. To examine the phenotype of neural-crest-derived cells in vagal and sacral pathways, we used antisera to Sox10, p75, Phox2b, and Hu, and transgenic mice in which the expression of green fluorescent protein was under the control of the Ret promoter. Sox10 was expressed prior to the emigration of vagal cells, whereas p75 was expressed shortly after their emigration. Most crest-derived cells that emigrated adjacent to somites 1–4 migrated along a pathway that was later followed by the vagus nerve. A sub-population of these vagal cells coalesced to form vagal ganglia, whereas others continued their migration towards the heart and gut. Cells that coalesced into vagal ganglia showed a different phenotype from cells in the migratory streams proximal and distal to the ganglia. Only a sub-population of the vagal cells that first entered the foregut expressed Phox2b or Ret. Sacral neural crest cells gave rise to pelvic ganglia and some neurons in the hindgut. The pathways of sacral neural crest cells were examined by using DβH-nlacZ mice. Sacral cells appeared to enter the distal hindgut around embryonic day 14.5. Very few of the previously demonstrated, but rare, neurons that were present in the large intestine of Ret null mutants and that presumably arose from the sacral neural crest expressed nitric oxide synthase, unlike their counterparts in Ret heterozygous mice.
Similar content being viewed by others
References
Baetge G, Gershon MD (1989) Transient catecholaminergic (TC) cells in the vagus nerves and bowel of fetal mice: relationship to the development of enteric neurons. Dev Biol 132:189–211
Baetge G, Pintar JE, Gershon MD (1990) Transiently catecholaminergic (TC) cells in the bowel of the fetal rat: precursors of noncatecholaminergic enteric neurons. Dev Biol 141:353–380
Bixby S, Kruger G, Mosher J, Joseph N, Morrison S (2002) Cell-intrinsic differences between stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity. Neuron 35:643–656
Bondurand N, Natarajan D, Thapar N, Atkins C, Pachnis V (2003) Neuron and glia generating progenitors of the mammalian enteric nervous system isolated from foetal and postnatal gut cultures. Development 130:6387–6400
Branchek TA, Gershon MD (1989) Time course of expression of neuropeptide Y, calcitonin gene-related peptide, and NADPH diaphorase activity in neurons of the developing murine bowel and the appearance of 5-hydroxytryptamine in mucosal enterochromaffin cells. J Comp Neurol 285:262–273
Burns AJ, Delalande JM (2005) Neural crest cell origin for intrinsic ganglia of the developing chicken lung. Dev Biol 277:63–79
Burns AJ, Le Douarin NM (1998) The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. Development 125:4335–4347
Burns AJ, Le Douarin NM (2001) Enteric nervous system development: analysis of the selective developmental potentialities of vagal and sacral neural crest cells using quail-chick chimeras. Anat Rec 262:16–28
Burns AJ, Champeval D, Le Douarin NM (2000) Sacral neural crest cells colonise aganglionic hindgut in vivo but fail to compensate for lack of enteric ganglia. Dev Biol 219:30–43
Cacalano G, Farinas I, Wang LC, Hagler K, Forgie A, Moore M, Armanini M, Phillips H, Ryan AM, Reichardt LF, Hynes M, Davies A, Rosenthal A (1998) GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21:53–62
Chalazonitis A, D'Autreaux F, Guha U, Pham TD, Faure C, Chen JJ, Roman D, Kan L, Rothman TP, Kessler JA, Gershon MD (2004) Bone morphogenetic protein-2 and −4 limit the number of enteric neurons but promote development of a TrkC-expressing neurotrophin-3-dependent subset. J Neurosci 24:4266–4282
Chan WY, Cheung CS, Yung KM, Copp AJ (2004) Cardiac neural crest of the mouse embryo: axial level of origin, migratory pathway and cell autonomy of the splotch (Sp2H) mutant effect. Development 131:3367–3379
Cheung M, Briscoe J (2003) Neural crest development is regulated by the transcription factor Sox9. Development 130:5681–5693
Conner PJ, Focke PJ, Noden DM, Epstein ML (2003) Appearance of neurons and glia with respect to the wavefront during colonization of the avian gut by neural crest cells. Dev Dyn 226:91–98
Doyle AM, Roberts DJ, Goldstein AM (2004) Enteric nervous system patterning in the avian hindgut. Dev Dyn 229:708–712
Durbec PL, Larsson-Blomberg LB, Schuchardt A, Costantini F, Pachnis V (1996) Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts. Development 122:349–358
Enomoto H, Araki T, Jackman A, Heuckeroth RO, Snider WD, Johnson EM Jr, Milbrandt J (1998) GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron 21:317–324
Enomoto H, Crawford PA, Gorodinsky A, Heuckeroth RO, Johnson EM Jr, Milbrandt J (2001) RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development 128:3963–3974
Epstein ML, Mikawa T, Brown AM, McFarlin DR (1994) Mapping the origin of the avian enteric nervous system with a retroviral marker. Dev Dyn 201:236–244
Erickson CA, Goins TL (2000) Sacral neural crest cell migration to the gut is dependent upon the migratory environment and not cell-autonomous migratory properties. Dev Biol 219:79–97
Fairman CL, Clagett-Dame M, Lennon VA, Epstein ML (1995) Appearance of neurons in the developing chick gut. Dev Dyn 204:192–201
Ferguson CA, Graham A (2004) Redefining the head-trunk interface for the neural crest. Dev Biol 269:70–80
Fu M, Lui VC, Sham MH, Pachnis V, Tam PK (2004) Sonic hedgehog regulates the proliferation, differentiation, and migration of enteric neural crest cells in gut. J Cell Biol 166:73–84
Gershon MD, Rothman TP, Joh TH, Teitelman GN (1984) Transient and differential expression of aspects of the catecholaminergic phenotype during development of the fetal bowel of rats and mice. J Neurosci 4:2269–2280
Gilmour DT, Maischein HM, Nüsslein-Volhard C (2002) Migration and function of a glial subtype in the vertebrate peripheral nervous system. Neuron 34:577–588
Honore SM, Aybar MJ, Mayor R (2003) Sox10 is required for the early development of the prospective neural crest in Xenopus embryos. Dev Biol 260:9–96
Kapur RP (2000) Colonization of the murine hindgut by sacral crest-derived neural precursors: experimental support for an evolutionarily conserved model. Dev Biol 227:146–155
Kapur RP, Yost C, Palmiter RD (1992) A transgenic model for studying development of the enteric nervous system in normal and aganglionic mice. Development 116:67–75
Kruger GM, Mosher JT, Tsai YH, Yeager KJ, Iwashita T, Gariepy CE, Morrison SJ (2003) Temporally distinct requirements for endothelin receptor B in the generation and migration of gut neural crest stem cells. Neuron 40:17–29
Le Douarin NM, Teillet MA (1973) The migration of neural crest cells to the wall of the digestive tract in avian embryo. J Embryol Exp Morphol 30:31–48
Luckensmeyer GB, Keast JR (1994) Projections from the prevertebral and major pelvic ganglia to the ileum and large intestine of the male rat. J Auton Nerv Syst 49:247–259
Luckensmeyer GB, Keast JR (1995) Immunohistochemical characterisation of sympathetic and parasympathetic pelvic neurons projecting to the distal colon in the male rat. Cell Tissue Res 281:551–559
Luckensmeyer GB, Keast JR (1998) Projections of pelvic autonomic neurons within the lower bowel of the male rat: an anterograde labelling study. Neuroscience 84:263–280
Mercer EH, Hoyle GW, Kapur RP, Brinster RL, Palmiter RD (1991) The dopamine beta-hydroxylase gene promoter directs expression of E. coli lacZ to sympathetic and other neurons in adult transgenic mice. Neuron 7:703–716
Moore MW, Klein RD, Farinas I, Sauer H, Armanini M, Phillips H, Reichardt LF, Ryan AM, Carver-Moore K, Rosenthal A (1996) Renal and neuronal abnormalities in mice lacking GDNF. Nature 382:76–79
Müller F, Rohrer H (2002) Molecular control of ciliary neuron development: BMPs and downstream transcriptional control in the parasympathetic lineage. Development 129:5707–5717
Natarajan D, Grigoriou M, Marcos-Gutierrez CV, Atkins C, Pachnis V (1999) Multipotential progenitors of the mammalian enteric nervous system capable of colonising aganglionic bowel in organ culture. Development 126:157–168
Natarajan D, Marcos-Gutierrez C, Pachnis V, de Graaff E (2002) Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis. Development 129:5151–5160
Norris PJ, Charles IG, Scorer CA, Emson PC (1995) Studies on the localization and expression of nitric oxide synthase using histochemical techniques. Histochem J 27:745–756
Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF (1999) The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature 399:366–370
Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H, Westphal H (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382:73–76
Pisano JM, Birren SJ (1999) Restriction of developmental potential during divergence of the enteric and sympathetic neuronal lineages. Development 126:2855–2868
Pomeranz HD, Gershon MD (1990) Colonization of the avian hindgut by cells derived from the sacral neural crest. Dev Biol 137:378–394
Pomeranz HD, Rothman TP, Gershon MD (1991) Colonization of the post-umbilical bowel by cells derived from the sacral neural crest: direct tracing of cell migration using an intercalating probe and a replication-deficient retrovirus. Development 111:647–655
Reedy MV, Faraco CD, Erickson CA (1998) The delayed entry of thoracic neural crest cells into the dorsolateral path is a consequence of the late emigration of melanogenic neural crest cells from the neural tube. Dev Biol 200:234–246
Reissmann E, Ernsberger U, Francis-West PH, Rueger D, Brickell PM, Rohrer H (1996) Involvement of bone morphogenetic protein-4 and bone morphogenetic protein-7 in the differentiation of the adrenergic phenotype in developing sympathetic neurons. Development 122:2079–2088
Sanchez MP, Silos-Santiago I, Frisen J, He B, Lira SA, Barbacid M (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382:70–73
Schneider C, Wicht H, Enderich J, Wegner M, Rohrer H (1999) Bone morphogenetic proteins are required in vivo for the generation of sympathetic neurons. Neuron 24:861–870
Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–383
Serbedzija GN, Burgan S, Fraser SE, Bronner-Fraser M (1991) Vital dye labelling demonstrates a sacral neural crest contribution to the enteric nervous system of chick and mouse embryos. Development 111:857–866
Shepherd IT, Raper JA (1999) Collapsin-1/semaphorin D is a repellent for chick ganglion of Remak axons. Dev Biol 212:42–53
Southard-Smith EM, Angrist M, Ellison JS, Agarwala R, Baxevanis AD, Chakravarti A, Pavan WJ (1999) The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res 9:215–225
Stewart AL, Anderson RB, Young HM (2003) Characterization of lacZ-expressing cells in the gut of embryonic and adult DbetaH-nlacZ mice. J Comp Neurol 464:208–219
Stone LM, Tan SS, Tam PP, Finger TE (2002) Analysis of cell lineage relationships in taste buds. J Neurosci 22:4522–4529
Sukegawa A, Narita T, Kameda T, Saitoh K, Nohno T, Iba H, Yasugi S, Fukuda K (2000) The concentric structure of the developing gut is regulated by Sonic hedgehog derived from endodermal epithelium. Development 127:1971–1980
Tollet J, Everett AW, Sparrow MP (2002) Development of neural tissue and airway smooth muscle in fetal mouse lung explants: a role for glial-derived neurotrophic factor in lung innervation. Am J Respir Cell Mol Biol 26:420–429
Tomac AC, Grinberg A, Huang SP, Nosrat C, Wang Y, Borlongan C, Lin SZ, Chiang YH, Olson L, Westphal H, Hoffer BJ (2000) Glial cell line-derived neurotrophic factor receptor alpha1 availability regulates glial cell line-derived neurotrophic factor signaling: evidence from mice carrying one or two mutated alleles. Neuroscience 95:1011–1023
Varley JE, Maxwell GD (1996) BMP-2 and BMP-4, but not BMP-6, increase the number of adrenergic cells which develop in quail trunk neural crest cultures. Exp Neurol 140:84–94
Wallace AS, Burns AJ (2005) Development of the enteric nervous system, smooth muscle and interstitial cells of Cajal in the human gastrointestinal tract. Cell Tissue Res 319:367–382
Wang HU, Anderson DJ (1997) Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18:383–396
Wanigasekara Y, Kepper ME, Keast JR (2003) Immunohistochemical characterisation of pelvic autonomic ganglia in male mice. Cell Tissue Res 311:175–185
Wilson YM, Richards KL, Ford-Perriss ML, Panthier JJ, Murphy M (2004) Neural crest cell lineage segregation in the mouse neural tube. Development 131:6153–6162
Yan H, Bergner AJ, Enomoto H, Milbrandt J, Newgreen DF, Young HM (2004) Neural cells in the esophagus respond to glial cell line-derived neurotrophic factor and neurturin, and are RET-dependent. Dev Biol 272:118–133
Yntema CL, Hammond WS (1954) The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J Comp Neurol 101:515–541
Young HM, Newgreen D (2001) Enteric neural crest-derived cells: origin, identification, migration, and differentiation. Anat Rec 262:1–15
Young HM, Ciampoli D, Hsuan J, Canty AJ (1999) Expression of ret-, p75NTR-, Phox2a-, Phox2b-, and tyrosine hydroxylase-immunoreactivity by undifferentiated neural crest-derived cells and different classes of enteric neurons in the embryonic mouse gut. Dev Dyn 216:137–152
Young HM, Bergner AJ, Müller T (2003) Acquisition of neuronal and glial markers by neural crest-derived cells in the mouse intestine. J Comp Neurol 456:1–11
Young HM, Bergner AJ, Anderson RB, Enomoto H, Milbrandt J, Newgreen DF, Whitington PM (2004) Dynamics of neural crest-derived cell migration in the embryonic mouse gut. Dev Biol 270:455–473
Acknowledgements
We thank Dr. Wood Yee Chan for valuable comments on the manuscript, Drs. Jeff Milbrandt and Hideki Enomoto for kindly supplying the Ret TGM mice, Ms. Annette Bergner for excellent technical assistance, Drs. Janet Keast and Yewlan Wanigasekara for advice on the location of pelvic ganglia, and Drs. Piers Emson, Miles Epstein and Jean-François Brunet for kindly providing antisera.
Author information
Authors and Affiliations
Corresponding author
Additional information
This study was supported by the National Health and Medical Research Council of Australia (project grants nos. 145628 and 350311, C.J. Martin Fellowship no. 007144, and Senior Research Fellowship no. 170224).
Rights and permissions
About this article
Cite this article
Anderson, R.B., Stewart, A.L. & Young, H.M. Phenotypes of neural-crest-derived cells in vagal and sacral pathways. Cell Tissue Res 323, 11–25 (2006). https://doi.org/10.1007/s00441-005-0047-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-005-0047-6