Journal
DEVELOPMENT
Volume 144, Issue 24, Pages 4704-4719Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.154336
Keywords
Kidney; Branching morphogenesis; Cell polarity; Transcriptional regulation; Gdnf-Gfra1-Ret pathway; Collecting duct
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM, France)
- European Community Seventh Framework Programme FP7 - Marie Curie Initial Training Network (ITN) Project [BOLD 238821]
- Centre National de la Recherche Scientifique (CNRS, France)
- Universite Pierre et Marie Curie
- Suomen Akatemia [206038, 121647, 250900, 260056]
- Centre of Excellence grant from the Suomen Akatemia [251314]
- European Community's Seventh Framework Programme FP7 [305608]
- Sigrid Juselius Stiftelse
- Ministere de l'Enseignement Superieur, de la Recherche Scientifique et des Technologies de l'Information et de la Communication
- European Renal Association - European Dialysis and Transplant Association (ERA-EDTA LTF-STF) [177-2014]
- Academy of Finland (AKA) [206038, 121647, 250900, 260056, 206038, 250900, 260056, 121647] Funding Source: Academy of Finland (AKA)
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Kidney development depends crucially on proper ureteric bud branching giving rise to the entire collecting duct system. The transcription factor HNF1B is required for the early steps of ureteric bud branching, yet the molecular and cellular events regulated by HNF1B are poorly understood. We report that specific removal of Hnf1b from the ureteric bud leads to defective cell-cell contacts and apicobasal polarity during the early branching events. High-resolution ex vivo imaging combined with a membranous fluorescent reporter strategy show decreased mutant cell rearrangements during mitosis-associated cell dispersal and severe epithelial disorganization. Molecular analysis reveals downregulation of Gdnf-Ret pathway components and suggests that HNF1B acts both upstream and downstream of Ret signaling by directly regulating Gfra1 and Etv5. Subsequently, Hnf1b deletion leads to massively mispatterned ureteric tree network, defective collecting duct differentiation and disrupted tissue architecture, which leads to cystogenesis. Consistently, mRNA-seq analysis shows that the most impacted genes encode intrinsic cell-membrane components with transporter activity. Our study uncovers a fundamental and recurring role of HNF1B in epithelial organization during early ureteric bud branching and in further patterning and differentiation of the collecting duct system in mouse.
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