GDNF signalling through the Ret receptor tyrosine kinase

Durbec, Pascale; Marcos-Gutierrez, Camelia V.; Kilkenny, Carol; Grigoriou, Maria; Wartiowaara, Kirmo; Suvanto, Petro; Smith, Dana; Ponder, Bruce A.J.; Costantini, Frank; Saarma, Märt; Sariola, Hannu; Pachnis, Vassilis

doi:10.1038/381789a0

Cited by 768 publications

(418 citation statements)

References 24 publications

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“…This hypothesis is further supported by the recent identi®cation of glial cell line-derived neurotrophic factor (GDNF) as a functional ligand for the ret RTK, since this molecule has a dramatic trophic e ect on several groups of CNS neurons, including motor neurons (Durbec et al, 1996b;Jing et al, 1996;Trupp et al, 1996). However, phenotypic analysis of mouse embryos and newborn animals mutated at the c-ret locus, failed to reveal any major abnormalities of motor neuron pools and sensory ganglia, although at this point we cannot exclude the possibility that subtle defects are present (CVM-G and VP; unpublished data).…”

Section: Expression During Embryogenesismentioning

confidence: 94%

The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis

et al. 1997

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The c-ret proto-oncogene, a member of the receptor tyrosine kinase gene superfamily, plays a critical role in the development of the excretory system and the enteric and autonomic nervous systems of mammalian embryos. To study the potential function of the c-ret locus in lower vertebrates, we have isolated its zebra®sh homologue, ret1 and established its expression pattern during embryogenesis. Ret1 mRNA ®rst appears during early somitogenesis in the presumptive brain, spinal cord and excretory system. Within the CNS, expression of ret1 is detected in primary motor and sensory (Rohon ± Beard) neurons. Ret1 transcripts are also expressed in subsets of neural crest cells and cranial ganglia as well as in the enteric nervous system. In the excretory system, expression is detected in the developing nephric duct and the pronephros. Our ®ndings reveal a remarkable similarity in the expression pattern of c-ret between higher and lower vertebrates, suggesting that the function of this locus has been conserved throughout vertebrate evolution. Furthermore, the conservation of ret1 expression in cell types which remain una ected by the mammalian c-ret mutations, such as motor and sensory neurons, suggests a function of this receptor in these cell lineages.

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Section: Expression During Embryogenesismentioning

confidence: 94%

The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis

et al. 1997

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“…Consistent with RET involvement in the induction of kidney morphogenesis, the RET knockout (7/7) mouse has kidney agenesis or severe dysgenesis (Schuchardt et al, 1994(Schuchardt et al, , 1996 as do mice lacking glial cell line-derived neurotrophic factor (GDNF) which encodes the soluble portion of the RET ligand (Moore et al, 1996;Pichel et al, 1996;SaÂ nchez et al, 1996). RET's proposed role as a transducer of mesenchymederived signals in kidney induction is supported by the localization of GDNF expression to the metanephric mesenchyme with highest expression in early developmental stages (Durbec et al, 1996a;Hellmich et al, 1996;Trupp et al, 1996).…”

Section: Introductionmentioning

confidence: 93%

Expression of RET 3′ splicing variants during human kidney development

1998

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The mature mammalian kidney arises through a series of reciprocal inductive interactions between two di erent cell groups, the ureteric bud epithelium and the metanephric mesenchyme. The RET receptor tyrosine kinase is required for induction and development of the metanephric kidney. Di erential splicing at the 3' end of RET results in transcripts encoding three isoforms that di er with respect to their C-terminal 9 (RET9), 51 (RET51) or 43 (RET43) amino acids. In vitro assays have identi®ed di erences in the abilities of the RET9 and RET51 isoforms to induce di erentiation suggesting functional di erences between these proteins. We examined the relative expression levels of the three RET 3' splicing variants in developing human kidney using semi-quantitative RT ± PCR. We observed consistent expression of the RET9 and RET43 variants in kidney samples spanning 7.5 through 24 weeks gestation. At early gestational ages (7.5 ± 8.5 weeks), RET51 expression was very low (+5%) compared to RET9; however, a rapid seven fold increase in expression was detected by 9 weeks. Our data suggest that RET51 may contribute to di erentiation-related events occurring after 8.5 weeks gestation rather than to induction of the human kidney.

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“…Activating mutations in the RET protooncogene have been described in all forms of MTC. RET is a receptor tyrosine kinase (Takahashi and Cooper, 1987) which interacts with glial cell linederived neurotrophic factor (GDNF) (Durbec et al, 1996;Jing et al, 1996;Treanor et al, 1996;Trupp et al, 1996) and a newly described, related protein, neurturin (NTN) (Buj-Bello et al, 1997;Creedon et al, 1997;Klein et al, 1997), via coreceptors GDNFR-a and NTNR-a respectively. Commonly, mutations in extracellular cysteine residues encoded by exons 10 and 11 of RET are associated with two inherited MTC syndromes, familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A (MEN 2A) (Donis-Keller et al, 1993;Mulligan et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells

et al. 1998

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Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the calcitonin secreting thyroid C-cells. Somatic and germline mutations in the RET proto-oncogene are associated with sporadic and inherited cases of MTC, respectively. The human MTC cell line, TT, can be di erentiated by activated raf-1. This di erentiation is characterized, in part, by down-regulation of the RET proto-oncogene. We now show that raf-1 induction is followed by activation of the downstream kinases MEK1/2 and ERK1/2 and that di erentiation is dependent on activation of MEK1/2. The concurrent down-regulation of RET appears to involve altered nuclear compartmentalization and transport of RET mRNA. Although RET is down-regulated during raf-1 mediated di erentiation, overexpression of activated RET alleles which resist down-regulation does not alter the raf-1 mediated di erentiation response. These data suggest that RET down-regulation is associated with, but not required, for raf-1 mediated MTC cell di erentiation and that the raf-1 signal transduction pathway plays a dominant role in promoting MTC cell di erentiation.

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GDNF signalling through the Ret receptor tyrosine kinase

Cited by 768 publications

References 24 publications

The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis

The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis

Expression of RET 3′ splicing variants during human kidney development

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells

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