Trends in Genetics
Volume 17, Issue 10, 1 October 2001, Pages 580-589
Journal home page for Trends in Genetics

Review
The RET receptor: function in development and dysfunction in congenital malformation

https://doi.org/10.1016/S0168-9525(01)02420-9Get rights and content

Abstract

Germline mutations in the RET proto-oncogene are responsible for two unrelated neural crest disorders: Hirschsprung disease, a congenital absence of the enteric nervous system in the hindgut, and multiple endocrine neoplasia type 2, a dominantly inherited cancer syndrome. Moreover, somatic rearrangements of RET are causally involved in the genesis of papillary thyroid carcinoma. The receptor tyrosine kinase encoded by the RET gene acts as the subunit of a multimolecular complex that binds four distinct ligands and activates a signalling network crucial for neural and kidney development. Over the past few years, a clearer picture of the mode of RET activation and of its multifaceted role during development has started to emerge. These findings, which provide new clues to the molecular mechanisms underlying RET signalling dysfunction in Hirschsprung disease, are summarized in this review.

Section snippets

The RET protein: the eccentric receptor tyrosine kinase with a cadherin domain

The human RET gene lies on chromosome band 10q11.2 and comprises 21 exons. Homologues of RET have been identified in higher and lower vertebrates, as well as in Drosophila melanogaster 4. RET codes for a transmembrane tyrosine kinase that has a structure similar to other receptor tyrosine kinases (RTKs), but it stands out by the presence of a cadherin domain in its extracellular region 5. Cadherins are Ca2+-dependent cell–cell adhesion proteins and their adhesive properties depend on a domain

RET associates with GFRα and forms receptors for GDNF family ligands

The family of glial-cell-line-derived neurotrophic factor ligands (GFLs) consist of four closely related homologues: Glial-cell-line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN) (reviewed in 12, 13; Fig. 1). They represent a new subclass of the transforming growth factor β (TGF-β) superfamily and, similarly to members of this family, GFLs are secreted disulfide-linked dimers that contain three disulfide bonds arranged in a typical configuration known

Role of GFL signalling during development

In situ hybridization and immunohistochemical analyses performed in rodent and human embryos have revealed that RET is expressed mostly in the developing nervous and urogenital systems 40, 41.

RET and Hirschsprung disease

Hirschsprung disease (HSCR), or colonic aganglionosis, is a common congenital disorder (prevalence: one in 5000 live births) leading to intestinal obstruction or chronic constipation (for a recent review see Ref. 56). The disease is characterized by the absence of intramural nervous plexuses along variable lengths of the hindgut. Most HSCR cases are sporadic; however, 15–20% are familial forms, and genetic analyses have led to the identification of mutations in genes coding for components of

Perspectives

Several questions arise from the results described above. First, what are the molecular components of the regulatory circuits that control RET expression? Interestingly, it has been recently reported that Pax3 and Sox10, two genes required during formation of the ENS and mutated in neural crest disorders, encode transcription factors that cooperate to activate transcription of RET 74. Second, which RET isoforms are required during neural, renal and spermatogonia development? What are the

Note added in proof

Recently, Grimm and co-workers showed that proteins of the p62 Dok family bind directly on the phosphorylated Tyr1062 of RET 75. Dok molecules contain both a pleckstrin and PTB domains. The authors provide evidence that Dok-4 and Dok-5 increase RET-dependent activation of the MAPK pathway and promote neuritic outgrowth of pheochromocytoma PC12 cells.

Acknowledgements

We thank C. Ibanez, L. Mulligan and P. Nony for reading the manuscript; M. Saarma for his insightful suggestions; and C. Ibanez, S. Lyonnet, B. Rossi, M. Takahashi and C. Thermes for sharing their results before publications. We also thank Mrs M. Billaud for the graphics. We apologize to our colleagues for failure to cite their work owing to space limitations. This work was supported by the Ligue Nationale Contre le Cancer (équipe Marc Billaud labélisée par LNCC).

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