RET receptor tyrosine kinase isoforms in kidney function and disease.
The RET proto-oncogene encodes two major isoforms, RET9 and RET51, which differ at the carboxyl-terminal. Loss-of-function mutations in RET result in gut aganglionosis while gain of function mutations result in cancer syndromes. From studies on transgenic mice, RET9 is important for early development of the kidney and the enteric nervous system. Little is known about the function of RET isoforms in later life. Here we report the expression of RET isoforms and its signalling complex, GDNF and GFRalpha1, in foetal and adult human kidneys. We found their expression in both the developing and the adult renal collecting system. We further show that only RET51 but not RET9 could promote the survival and tubulogenesis of mIMCD3 (mouse inner medullary collecting duct) cells in collagen gel. Our results agree with the hypothesis that RET51 signalling is related to differentiation events in later kidney organogenesis. In addition, it may also have a function in the adult kidney. We further extend our study by showing increased RET and GDNF expression in collecting duct cysts of polycystic kidney patients. This suggests that GDNF/RET signalling may contribute to proliferation of the collecting duct epithelium in an autocrine/paracrine manner.
Lee
Davy Chun Wai
DC
Department of Paediatrics and Centre of Human Development and Birth Defects, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
Chan
Kwok Wah
KW
Chan
Siu Yuen
SY
D000368:Aged; D017398:Alternative Splicing; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D017931:DNA Primers / Q000737:chemistry; D029721:Drosophila Proteins; D005314:Embryonic and Fetal Development; D004848:Epithelium / Q000378:metabolism; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007527:Isoenzymes; D007668:Kidney / Q000201:enzymology*; D008875:Middle Aged; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000201:enzymology* / Q000473:pathology; D011233:Precipitin Tests; D011247:Pregnancy; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D015347:RNA Probes; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection
D017931:DNA Primers; D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007527:Isoenzymes; C000715470:MAS1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015347:RNA Probes; D012333:RNA, Messenger; D003094:Collagen; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila