HNF1B Controls Epithelial Organization and Cell Polarity During Ureteric Bud Branching and Collecting Duct Morphogenesis

Development. 2017 Dec 15;144(24):4704-4719. doi: 10.1242/dev.154336. Epub 2017 Nov 20.

Abstract

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.

Keywords: Branching morphogenesis; Cell polarity; Collecting duct; Gdnf-Gfrα1-Ret pathway; Kidney; Transcriptional regulation.

MeSH terms

  • Animals
  • Cell Adhesion / genetics
  • Cell Polarity / genetics*
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Hepatocyte Nuclear Factor 1-beta / genetics*
  • Hepatocyte Nuclear Factor 1-beta / metabolism
  • Kidney Tubules, Collecting / embryology*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / metabolism
  • Organ Culture Techniques
  • PAX2 Transcription Factor / biosynthesis
  • Signal Transduction / genetics
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases
  • Ureter / embryology*
  • Urogenital Abnormalities / embryology*
  • Urogenital Abnormalities / genetics*

Substances

  • DNA-Binding Proteins
  • Etv5 protein, mouse
  • Gfra1 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Hnf1b protein, mouse
  • Nuclear Proteins
  • PAX2 Transcription Factor
  • Pax2 protein, mouse
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1-beta
  • Trim27 protein, mouse
  • Ubiquitin-Protein Ligases