Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UNIPROT:P41181 (
collecting duct
)
5,183
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The antagonism between Mdm2 and its close homolog Mdm4 (also known as MdmX) and p53 is vital for embryogenesis and organogenesis. Previously, we demonstrated that targeted disruption of Mdm2 in the Hoxb7+ ureteric bud (Ub) lineage, which gives rise to the renal collecting system, causes renal hypodysplasia culminating in perinatal lethality. In this study, we examine the unique role of Mdm4 in establishing the
collecting duct
system of the murine kidney. Hoxb7Cre driven loss of Mdm4 in the Ub lineage (Ub
Mdm4-/-
) disrupts branching morphogenesis and triggers UB cell apoptosis. Ub
Mdm4-/-
kidneys exhibit abnormally dilated Ub tips while the medulla is hypoplastic. These structural alterations result in secondary depletion of nephron progenitors and nascent nephrons. As a result, newborn Ub
Mdm4-/-
mice have hypo-dysplastic kidneys. Transcriptional profiling revealed downregulation of the Ret-
tyrosine kinase
pathway components, Gdnf, Wnt11, Sox8, Etv4 and Cxcr4 in the Ub
Mdm4-/-
mice relative to controls. Moreover, the expression levels of the canonical Wnt signaling members Axin2 and Wnt9b are downregulated. Mdm4 deletion upregulated p53 activity and p53-target gene expression including Cdkn1a (p21), Gdf15, Ccng1, PERP, and Fas. Germline loss of p53 in Ub
Mdm4-/-
mice largely rescues kidney development and terminal differentiation of the
collecting duct
. We conclude that Mdm4 plays a unique and vital role in Ub branching morphogenesis and collecting system development.
...
PMID:Mdm4 controls ureteric bud branching via regulation of p53 activity. 3246 96
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