Document Detail

Hnf1b and Pax2 cooperate to control different pathways in kidney and ureter morphogenesis.
MedLine Citation:
PMID:  22511595     Owner:  NLM     Status:  Publisher    
The transcription factors HNF1B and Pax2, co-expressed in the Wolffian duct and ureteric bud epithelia, play essential roles during the early steps of mouse kidney development. In humans, heterozygous mutations in these genes display a number of common kidney phenotypes, including hypoplasia and multicystic hypoplastic kidneys. Moreover, a high prevalence of mutations either in HNF1B or PAX2 has been observed in children with renal hypodysplasia. To gain a better understanding of Hnf1b and Pax2 interactions in vivo, we generated compound heterozygous mice for Hnf1b and Pax2 null alleles. We show here that compound heterozygous mutants display phenotypes similar to severe Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT), including strong kidney hypoplasia, caudal ectopic aborted ureter buds, duplex kidneys, megaureters and hydronephrosis. At a molecular level, compound mutants show a delay in nephron segment and medullar interstitial differentiation, increased apoptosis and a transient decrease in Lim1 and Wnt4 expression. We also observe a perturbation of smooth muscle differentiation around the ureter associated with a local downregulation in transcript levels of Bmp4 and Tbx18, two key regulators involved in ureter smooth muscle formation, thus explaining at least in part megaureters. These results together uncover a novel role of Hnf1b as a modifier of the Pax2 haploinsufficient phenotype and show that these two transcription factors operate in common pathways governing both kidney morphogenesis and ureter differentiation. This mouse model should provide new insights into the pathogenic mechanisms of human CAKUT, the most frequent developmental defect identified in newborns.
Mélanie Paces-Fessy; Mélanie Fabre; Céline Lesaulnier; Silvia Cereghini
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-17
Journal Detail:
Title:  Human molecular genetics     Volume:  -     ISSN:  1460-2083     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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