Trends in Genetics
ReviewThe RET receptor: function in development and dysfunction in congenital malformation
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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