{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:55:32Z","timestamp":1792738532424,"version":"4.5.0"},"reference-count":53,"publisher":"The Company of Biologists","issue":"22","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2002,11,15]]},"abstract":"<jats:p>The majority of neurones and glia of the enteric nervous system (ENS) are derived from the vagal neural crest. Shortly after emigration from the neural tube, ENS progenitors invade the anterior foregut and, migrating in a rostrocaudal direction, colonise in an orderly fashion the rest of the foregut, the midgut and the hindgut. We provide evidence that activation of the receptor tyrosine kinase RET by glial cell line-derived neurotrophic factor (GDNF) is required for the directional migration of ENS progenitors towards and within the gut wall. We find that neural crest-derived cells present within foetal small intestine explants migrate towards an exogenous source of GDNF in a RET-dependent fashion. Consistent with an in vivo role of GDNF in the migration of ENS progenitors, we demonstrate that Gdnf is expressed at high levels in the gut of mouse embryos in a spatially and temporally regulated manner. Thus, during invasion of the foregut by vagal-derived neural crest cells, expression of Gdnf was restricted to the mesenchyme of the stomach, ahead of the invading NC cells. Twenty-four hours later and as the ENS progenitors were colonising the midgut,Gdnf expression was upregulated in a more posterior region \u2014the caecum anlage. In further support of a role of endogenous GDNF in enteric neural crest cell migration, we find that in explant cultures GDNF produced by caecum is sufficient to attract NC cells residing in more anterior gut segments. In addition, two independently generated loss-of-function alleles of murine Ret, Ret.k\u2014 and miRet51, result in characteristic defects of neural crest cell migration within the developing gut. Finally, we identify phosphatidylinositol-3 kinase and the mitogen-activated protein kinase signalling pathways as playing crucial roles in the migratory response of enteric neural crest cells to GDNF.<\/jats:p>","DOI":"10.1242\/dev.129.22.5151","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T14:49:08Z","timestamp":1619448548000},"page":"5151-5160","source":"Crossref","is-referenced-by-count":293,"title":["Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis"],"prefix":"10.1242","volume":"129","author":[{"given":"Dipa","family":"Natarajan","sequence":"first","affiliation":[{"name":"Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camelia","family":"Marcos-Gutierrez","sequence":"additional","affiliation":[{"name":"Present address: GlaxoSmithKline Biologicals, Rue de l'Institut 89, B-1330 Rixensart, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassilis","family":"Pachnis","sequence":"additional","affiliation":[{"name":"Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"de Graaff","sequence":"additional","affiliation":[{"name":"Present addresses: Department of Clinical Genetics, Erasmus University, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042611413524700_REF1","doi-asserted-by":"crossref","unstructured":"Airaksinen, M. S., Titievsky, A. and Saarma, M.(1999). GDNF family neurotrophic factor signaling: four masters,one servant? Mol. Cell. Neurosci.13,313-325.","DOI":"10.1006\/mcne.1999.0754"},{"key":"2021042611413524700_REF2","doi-asserted-by":"crossref","unstructured":"Atwal, J. K., Massie, B., Miller, F. D. and Kaplan, D. R.(2000). The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron27,265-277.","DOI":"10.1016\/S0896-6273(00)00035-0"},{"key":"2021042611413524700_REF3","doi-asserted-by":"crossref","unstructured":"Baetge, G. and Gershon, M. D. (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.","DOI":"10.1016\/0012-1606(89)90217-0"},{"key":"2021042611413524700_REF4","doi-asserted-by":"crossref","unstructured":"Baloh, R. H., Enomoto, H., Johnson, E. M., Jr and Milbrandt,J. (2000). The GDNF family ligands and receptors -implications for neural development. Curr. Opin. Neurobiol.10,103-110.","DOI":"10.1016\/S0959-4388(99)00048-3"},{"key":"2021042611413524700_REF5","doi-asserted-by":"crossref","unstructured":"Besset, V., Scott, R. P. and Ibanez, C. F.(2000). Signaling complexes and protein-protein interactions involved in the activation of the ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase. J. Biol. Chem.275,39159-39166.","DOI":"10.1074\/jbc.M006908200"},{"key":"2021042611413524700_REF6","doi-asserted-by":"crossref","unstructured":"Britsch, S., Goerich, D. E., Riethmacher, D., Peirano, R. I.,Rossner, M., Nave, K. A., Birchmeier, C. and Wegner, M.(2001). The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev.15, 66-78.","DOI":"10.1101\/gad.186601"},{"key":"2021042611413524700_REF7","doi-asserted-by":"crossref","unstructured":"Brookes, S. J. (2001). Classes of enteric nerve cells in the guinea-pig small intestine. Anat. Rec.262, 58-70.","DOI":"10.1002\/1097-0185(20010101)262:1<58::AID-AR1011>3.0.CO;2-V"},{"key":"2021042611413524700_REF8","doi-asserted-by":"crossref","unstructured":"Chen, Z., Chai, Y., Cao, L., Huang, A., Cui, R., Lu, C. and He,C. (2001). Glial cell line-derived neurotrophic factor promotes survival and induces differentiation through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathway respectively in PC12 cells. Neuroscience104,593-598.","DOI":"10.1016\/S0306-4522(01)00093-8"},{"key":"2021042611413524700_REF9","doi-asserted-by":"crossref","unstructured":"de Graaff, E., Srinivas, S., Kilkenny, C., D'Agati, V., Mankoo,B. S., Costantini, F. and Pachnis, V. (2001). Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev.15,2433-2444.","DOI":"10.1101\/gad.205001"},{"key":"2021042611413524700_REF10","unstructured":"De Vita, G., Melillo, R. M., Carlomagno, F., Visconti, R.,Castellone, M. D., Bellacosa, A., Billaud, M., Fusco, A., Tsichlis, P. N. and Santoro, M. (2000). Tyrosine 1062 of RET-MEN2A mediates activation of Akt (protein kinase B) and mitogen-activated protein kinase pathways leading to PC12 cell survival. Cancer Res.60,3727-3731."},{"key":"2021042611413524700_REF11","doi-asserted-by":"crossref","unstructured":"Decker, R. A., Peacock, M. L. and Watson, P.(1998). Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum. Mol. Genet.7,129-134.","DOI":"10.1093\/hmg\/7.1.129"},{"key":"2021042611413524700_REF12","doi-asserted-by":"crossref","unstructured":"Duchek, P. and Rorth, P. (2001). Guidance of cell migration by EGF receptor signaling during Drosophila oogenesis.Science291,131-133.","DOI":"10.1126\/science.291.5501.131"},{"key":"2021042611413524700_REF13","doi-asserted-by":"crossref","unstructured":"Duchek, P., Somogyi, K., Jekely, G., Beccari, S. and Rorth,P. (2001). Guidance of cell migration by the drosophila pdgf\/vegf receptor. Cell107, 17-26.","DOI":"10.1016\/S0092-8674(01)00502-5"},{"key":"2021042611413524700_REF14","doi-asserted-by":"crossref","unstructured":"Durbec, P. L., Larsson-Blomberg, L. B., Schuchardt, A.,Costantini, F. and Pachnis, V. (1996). Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts. Development122,349-358.","DOI":"10.1242\/dev.122.1.349"},{"key":"2021042611413524700_REF15","unstructured":"Gershon, M. D., Kirchgessner, A. L. and Wade, P. R.(1994). Functional anatomy of the enteric nervous system. InPhysiology of the Gastrointestinal Tract, Vol.1 (ed. L. R. Johnson), pp.381-422. New York: Raven Press."},{"key":"2021042611413524700_REF16","doi-asserted-by":"crossref","unstructured":"Hashino, E., Shero, M., Junghans, D., Rohrer, H., Milbrandt, J. and Johnson, E. M., Jr (2001). GDNF and neurturin are target-derived factors essential for cranial parasympathetic neuron development. Development128,3773-3782.","DOI":"10.1242\/dev.128.19.3773"},{"key":"2021042611413524700_REF17","doi-asserted-by":"crossref","unstructured":"Hayashi, H., Ichihara, M., Iwashita, T., Murakami, H., Shimono,Y., Kawai, K., Kurokawa, K., Murakumo, Y., Imai, T., Funahashi, H., Nakao, A. and Takahashi, M. (2000). Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Oncogene19,4469-4475.","DOI":"10.1038\/sj.onc.1203799"},{"key":"2021042611413524700_REF18","doi-asserted-by":"crossref","unstructured":"Ishiguro, Y., Iwashita, T., Murakami, H., Asai, N., Iida, K.,Goto, H., Hayakawa, T. and Takahashi, M. (1999). The role of amino acids surrounding tyrosine 1062 in ret in specific binding of the shc phosphotyrosine-binding domain. Endocrinology140,3992-3998.","DOI":"10.1210\/endo.140.9.7003"},{"key":"2021042611413524700_REF19","doi-asserted-by":"crossref","unstructured":"Kapur, R. P., Yost, C. and Palmiter, R. D.(1992). A transgenic model for studying development of the enteric nervous system in normal and aganglionic mice.Development116,167-175.","DOI":"10.1242\/dev.116.1.167"},{"key":"2021042611413524700_","doi-asserted-by":"crossref","unstructured":"Le Douarin, N. and Kalcheim, C. (1999).The Neural Crest. Cambridge: Cambridge University Press.","DOI":"10.1017\/CBO9780511897948"},{"key":"2021042611413524700_REF21","doi-asserted-by":"crossref","unstructured":"Le Douarin, N. M. and Teillet, M. A. (1973). The migration of neural crest cells to the wall of the digestive tract in avian embryo. J. Embryol. Exp. Morphol.30, 31-48.","DOI":"10.1242\/dev.30.1.31"},{"key":"2021042611413524700_REF22","doi-asserted-by":"crossref","unstructured":"Mograbi, B., Bocciardi, R., Bourget, I., Juhel, T., Farahi-Far,D., Romeo, G., Ceccherini, I. and Rossi, B. (2001). The sensitivity of activated Cys Ret mutants to glial cell line-derived neurotrophic factor is mandatory to rescue neuroectodermic cells from apoptosis. Mol. Cell. Biol.21,6719-6730.","DOI":"10.1128\/MCB.21.20.6719-6730.2001"},{"key":"2021042611413524700_REF23","doi-asserted-by":"crossref","unstructured":"Moore, M. W., Klein, R. D., Farinas, I., Sauer, H., Armanini,M., Phillips, H., Reichardt, L. F., Ryan, A. M., Carver-Moore, K. and Rosenthal, A. (1996). Renal and neuronal abnormalities in mice lacking GDNF. Nature382, 76-79.","DOI":"10.1038\/382076a0"},{"key":"2021042611413524700_REF24","doi-asserted-by":"crossref","unstructured":"Mulligan, L. M., Eng, C., Attie, T., Lyonnet, S., Marsh, D. J.,Hyland, V. J., Robinson, B. G., Frilling, A., Verellen-Dumoulin, C., Safar, A. et al. (1994). Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum. Mol. Genet.3,2163-2167.","DOI":"10.1093\/hmg\/3.12.2163"},{"key":"2021042611413524700_REF25","doi-asserted-by":"crossref","unstructured":"Natarajan, D., Grigoriou, M., Marcos-Gutierrez, C. V., Atkins,C. and Pachnis, V. (1999). Multipotential progenitors of the mammalian enteric nervous system capable of colonising aganglionic bowel in organ culture. Development126,157-168.","DOI":"10.1242\/dev.126.1.157"},{"key":"2021042611413524700_REF26","doi-asserted-by":"crossref","unstructured":"O'Connor, R. and Tessier-Lavigne, M. (1999). Identification of maxillary factor, a maxillary process-derived chemoattractant for developing trigeminal sensory axons.Neuron24,165-178.","DOI":"10.1016\/S0896-6273(00)80830-2"},{"key":"2021042611413524700_REF27","doi-asserted-by":"crossref","unstructured":"Pachnis, V., Mankoo, B. and Costantini, F.(1993). Expression of the c-ret proto-oncogene during mouse embryogenesis. Development119,1005-1017.","DOI":"10.1242\/dev.119.4.1005"},{"key":"2021042611413524700_REF28","doi-asserted-by":"crossref","unstructured":"Parisi, M. A. and Kapur, R. P. (2000). Genetics of Hirschsprung disease. Curr. Opin. Pediatr.12,610-617.","DOI":"10.1097\/00008480-200012000-00017"},{"key":"2021042611413524700_REF29","doi-asserted-by":"crossref","unstructured":"Pham, T. D., Gershon, M. D. and Rothman, T. P.(1991). Time of origin of neurons in the murine enteric nervous system: sequence in relation to phenotype. J. Comp. Neurol.314,789-798.","DOI":"10.1002\/cne.903140411"},{"key":"2021042611413524700_REF30","unstructured":"Saarma, M. (2000). GDNF - a stranger in the TGF-beta superfamily? Eur. J. Biochem.267,6968-6971."},{"key":"2021042611413524700_REF31","doi-asserted-by":"crossref","unstructured":"Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini,F. and Pachnis, V. (1994). Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret.Nature367,380-383.","DOI":"10.1038\/367380a0"},{"key":"2021042611413524700_REF32","doi-asserted-by":"crossref","unstructured":"Segouffin-Cariou, C. and Billaud, M. (2000). Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase\/AKT signaling pathway. J. Biol. Chem.275,3568-3576.","DOI":"10.1074\/jbc.275.5.3568"},{"key":"2021042611413524700_REF33","unstructured":"Sidebotham, E. L., Woodward, M. N., Kenny, S. E., Lloyd, D. A.,Vaillant, C. R. and Edgar, D. H. (2001). Assessment of protein gene product 9.5 as a marker of neural crest-derived precursor cells in the developing enteric nervous system. Pediatr. Surg. Int.17,304-307."},{"key":"2021042611413524700_REF34","doi-asserted-by":"crossref","unstructured":"Song, H. and Poo, M. (2001). The cell biology of neuronal navigation. Nat. Cell Biol.3, E81-E88.","DOI":"10.1038\/35060164"},{"key":"2021042611413524700_REF35","doi-asserted-by":"crossref","unstructured":"Southard-Smith, E. M., Kos, L. and Pavan, W. J.(1998). Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat. Genet.18, 60-64.","DOI":"10.1038\/ng0198-60"},{"key":"2021042611413524700_REF36","doi-asserted-by":"crossref","unstructured":"Takahashi, M. (2001). The GDNF\/RET signaling pathway and human diseases. Cytokine Growth Factor Rev.12,361-373.","DOI":"10.1016\/S1359-6101(01)00012-0"},{"key":"2021042611413524700_REF37","doi-asserted-by":"crossref","unstructured":"Takahashi, M. and Cooper, G. M. (1987). ret transforming gene encodes a fusion protein homologous to tyrosine kinases.Mol. Cell. Biol.7,1378-1385.","DOI":"10.1128\/MCB.7.4.1378"},{"key":"2021042611413524700_REF38","unstructured":"Takahashi, M., Buma, Y., Iwamoto, T., Inaguma, Y., Ikeda, H. and Hiai, H. (1988). Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene3,571-578."},{"key":"2021042611413524700_REF39","doi-asserted-by":"crossref","unstructured":"Taraviras, S. and Pachnis, V. (1999). Development of the mammalian enteric nervous system. Curr. Opin. Genet. Dev.9,321-327.","DOI":"10.1016\/S0959-437X(99)80048-3"},{"key":"2021042611413524700_REF40","doi-asserted-by":"crossref","unstructured":"Taraviras, S., Marcos-Gutierrez, C. V., Durbec, P., Jani, H.,Grigoriou, M., Sukumaran, M., Wang, L. C., Hynes, M., Raisman, G. and Pachnis,V. (1999). Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system.Development126,2785-2797.","DOI":"10.1242\/dev.126.12.2785"},{"key":"2021042611413524700_REF41","doi-asserted-by":"crossref","unstructured":"Tessier-Lavigne, M., Placzek, M., Lumsden, A. G., Dodd, J. and Jessell, T. M. (1988). Chemotropic guidance of developing axons in the mammalian central nervous system. Nature336,775-778.","DOI":"10.1038\/336775a0"},{"key":"2021042611413524700_REF42","doi-asserted-by":"crossref","unstructured":"Trainor, P. A. and Krumlauf, R. (2000). Patterning the cranial neural crest: hindbrain segmentation and Hox gene plasticity. Nat. Rev. Neurosci.1, 116-124.","DOI":"10.1038\/35039056"},{"key":"2021042611413524700_REF43","unstructured":"Tsuzuki, T., Takahashi, M., Asai, N., Iwashita, T., Matsuyama,M. and Asai, J. (1995). Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues.Oncogene10,191-198."},{"key":"2021042611413524700_REF44","doi-asserted-by":"crossref","unstructured":"van Weering, D. H. and Bos, J. L. (1997). Glial cell line-derived neurotrophic factor induces Ret-mediated lamellipodia formation. J. Biol. Chem.272,249-254.","DOI":"10.1074\/jbc.272.1.249"},{"key":"2021042611413524700_REF45","doi-asserted-by":"crossref","unstructured":"van Weering, D. H. and Bos, J. L. (1998). Signal transduction by the receptor tyrosine kinase Ret. Recent Results Cancer Res.154,271-281.","DOI":"10.1007\/978-3-642-46870-4_18"},{"key":"2021042611413524700_REF46","doi-asserted-by":"crossref","unstructured":"Wehrle-Haller, B. and Weston, J. A. (1997). Receptor tyrosine kinase-dependent neural crest migration in response to differentially localized growth factors. BioEssays19,337-345.","DOI":"10.1002\/bies.950190411"},{"key":"2021042611413524700_REF47","doi-asserted-by":"crossref","unstructured":"Wehrle-Haller, B., Meller, M. and Weston, J. A.(2001). Analysis of melanocyte precursors in Nf1 mutants reveals that MGF\/KIT signaling promotes directed cell migration independent of its function in cell survival. Dev. Biol.232,471-483.","DOI":"10.1006\/dbio.2001.0167"},{"key":"2021042611413524700_REF48","doi-asserted-by":"crossref","unstructured":"Wilkinson, D. G. (2001). Multiple roles of EPH receptors and ephrins in neural development. Nat. Rev. Neurosci.2,155-164.","DOI":"10.1038\/35058515"},{"key":"2021042611413524700_REF49","doi-asserted-by":"crossref","unstructured":"Worley, D. S., Pisano, J. M., Choi, E. D., Walus, L., Hession,C. A., Cate, R. L., Sanicola, M. and Birren, S. J. (2000). Developmental regulation of GDNF response and receptor expression in the enteric nervous system. Development127,4383-4393.","DOI":"10.1242\/dev.127.20.4383"},{"key":"2021042611413524700_REF50","doi-asserted-by":"crossref","unstructured":"Yntema, C. L. and Hammond, W. S. (1954). The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J. Comp. Neurol.101,515-542.","DOI":"10.1002\/cne.901010212"},{"key":"2021042611413524700_REF51","doi-asserted-by":"crossref","unstructured":"Young, H. M., Hearn, C. J., Ciampoli, D., Southwell, B. R.,Brunet, J. and Newgreen, D. F. (1998). A single rostrocaudal colonization of the rodent intestine by enteric neuron precursors is revealed by the expression of phox2b, ret, and p75 and by explants grown under the kidney capsule or in organ culture. Dev. Biol.202, 67-84.","DOI":"10.1006\/dbio.1998.8987"},{"key":"2021042611413524700_REF52","doi-asserted-by":"crossref","unstructured":"Young, H. M., Ciampoli, D., Hsuan, J. and Canty, A. J.(1999). Expression of Ret-, p75(NTR)-, 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.","DOI":"10.1002\/(SICI)1097-0177(199910)216:2<137::AID-DVDY5>3.0.CO;2-6"},{"key":"2021042611413524700_REF53","doi-asserted-by":"crossref","unstructured":"Young, H. M., Hearn, C. J., Farlie, P. G., Canty, A. J., Thomas,P. Q. and Newgreen, D. F. (2001). GDNF Is a Chemoattractant for Enteric Neural Cells. Dev. Biol.229,503-516.","DOI":"10.1006\/dbio.2000.0100"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/129\/22\/5151\/1210638\/5151.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/129\/22\/5151\/1210638\/5151.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T13:03:06Z","timestamp":1671973386000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/129\/22\/5151\/51928\/Requirement-of-signalling-by-receptor-tyrosine"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,11,15]]},"references-count":53,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2002,11,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.129.22.5151","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2002,11,15]]}}}