GDNF signalling through the Ret receptor tyrosine kinase.
Mutational analysis in humans and mice has demonstrated that the Ret, the product of the c-ret proto-oncogene, a member of the receptor tyrosine kinase (RTK) superfamily, is essential for development of the enteric nervous system and kidney. Despite the established role of Ret in mammalian embryogenesis, its cognate ligand(s) is currently unknown. Here we demonstrate, by using a Xenopus embryo bioassay, that glial-cell-line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor (TGF)-beta superfamily, signals through the Ret RTK. Furthermore, using explant cultures from wild-type and Ret-deficient mouse embryos, we show that normal c-ret function is necessary for GDNF signalling in the peripheral nervous system. Our data strongly suggest that Ret is a functional receptor for GDNF, and that GDNF, in addition to its potential role in the differentiation and survival of central nervous system neurons, has profound effects on kidney organogenesis and the development of the peripheral nervous system.
Durbec
P
P
Division of Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
Marcos-Gutierrez
C V
CV
Kilkenny
C
C
Grigoriou
M
M
Wartiowaara
K
K
Suvanto
P
P
Smith
D
D
Ponder
B
B
Costantini
F
F
Saarma
M
M
D000818:Animals; D029721:Drosophila Proteins; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014981:Xenopus
D029721:Drosophila Proteins; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; C495001:Ret protein, rat