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Title:
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Critical and distinct roles for key RET tyrosine docking sites in renal development
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Author:
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Jain, Sanjay; Encinas Martín, Mario; Johnson, Eugene M.; Milbrandt, Jeffrey
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Notes:
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Molecular mechanisms that lead to congenital anomalies of kidneys and the lower urinary tract (CAKUT) are
poorly understood. To elucidate the molecular basis for signaling specificity of GDNF-mediated RET signaling
in kidney development, we characterized mice that exclusively express either the human RET9 or RET51
isoform, or express these isoforms with individual mutations in docking tyrosines for PTB and
SH2-domain-containing adaptors Src (Y981), PLC (Y1015), and Shc (Y1062). Our results provide evidence for
differential and isoform-specific roles of these docking sites in murine kidney development. Homozygous
RetRET9 and RetRET51 mice were viable and show normally developed kidneys, indicating redundant roles of
human RET isoforms in murine kidney development. In the context of the RET51 isoform, only mutation of
the docking Tyr 1015 (Y1015F) resulted in severe renal anomalies. These included bilateral megaureters and
multicystic kidneys that were caused by supernumerary ureteric buds that fail to separate from the wolffian
duct as well as decreased branching morphogenesis. Similar kidney and ureter defects were observed in
RET9(Y1015F) mice that contain the Y1015F mutation in the RET9 isoform. Interestingly, loss of
RET9(Y1062)-mediated AKT/MAPK activation resulted in renal agenesis or kidney rudiments, whereas
mutation of this residue in RET51 had no obvious effect on AKT/MAPK activity and renal development.
These results reveal novel roles of key RET-dependent signaling pathways in embryonic kidney development
and provide murine models and new insights into the molecular basis for CAKUT. |
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Subject(s):
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-Ronyons--Malalties |
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Rights:
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(c) Cold Spring Harbor Laboratory Press, 2006
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
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Document type:
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article
publishedVersion |
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Published by:
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Cold Spring Harbor Laboratory Press
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Share:
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