vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis

Abstract

Mouse metanephric kidney development begins with the induction of the ureteric bud (UB) from the caudal portion of the Wolffian duct by metanephric mesenchymal signals. While the UB undergoes branching morphogenesis to generate the entire urinary collecting system and the ureter, factors secreted by the UB tips induce surrounding mesenchymal cells to convert into epithelia and form the nephrons, the functional units of the kidney. Epithelial branching morphogenesis and nephrogenesis are therefore tightly orchestrated; defects in either of these processes lead to severe kidney phenotypes ranging from hypoplasia to complete aplasia. However, the underlying regulatory networks have been only partially elucidated. Here, we identify the transcription factor vHNF1 (HNF1β) as a crucial regulator of these early developmental events. Initially involved in timing outgrowth of the UB and subsequent branching, vHNF1 is also required for nephric duct epithelial maintenance, Müllerian duct formation and early nephrogenesis. Mosaic analyses further suggest a cell-autonomous requirement for vHNF1 in the acquisition of a specialized tip domain and branching morphogenesis. vHNF1 exerts these intricate functions at least in part through the direct control of key regulatory molecules involved in different aspects of early kidney development. Notably, vHNF1 acting directly upstream of Wnt9b appears to orchestrate Wnt signaling action in the mesenchymal-epithelial transitions underlying the initiation of nephrogenesis. These results demonstrate that vHNF1 is an essential transcriptional regulator that, in addition to the known later functions in normal duct morphogenesis, plays a crucial role during the earliest stages of urogenital development and provide novel insights into the regulatory circuits controlling events.

Hepatocyte nuclear factor 1β controls nephron tubular development

“…In agreement with previous studies (Harding et al, 2011;Lokmane et al, 2010;McMahon et al, 2008), immunofluorescence experiments showed that HNF1β was not expressed in cap mesenchyme ( Fig. 2A, arrow).…”

“…For instance, it has been shown that germline inactivation of Hnf1b is embryonic lethal (E7.5) (Barbacci et al, 1999;Coffinier et al, 1999a). During kidney development, the lack of this gene in the UB leads to defective UB branching and to the absence of mesenchymal to epithelial transition due to defective expression of key genes including Wnt9b (Lokmane et al, 2010) (our unpublished observations). In parallel, it has been shown that deletion of Hnf1b in already formed, still elongating, tubular segments leads to a severe polycystic kidney phenotype (Gresh et al, 2004;Verdeguer et al, 2010).…”

“…The study of animal models for Hnf1b deficiency in renal development and maturation has helped us to understand some of the functions of HNF1β (Bohn et al, 2003;Gresh et al, 2004;Hiesberger et al, 2004;Lokmane et al, 2010;Sun et al, 2004;Verdeguer et al, 2010;Wu et al, 2004). The phenotype of mice lacking Hnf1b depends very much on exactly when (developmental timing) and where (which tissue compartment) the gene is inactivated.…”

Cell Biology of Ureter Development

“…30,31 Prominent ND/UB apoptosis and impaired UB formation occurs in embryos lacking HNF1B (also known as vHNF). 32 This transcription factor is normally expressed in the ND/UB, where it may directly upregulate PAX2. 32 …”

“…32 This transcription factor is normally expressed in the ND/UB, where it may directly upregulate PAX2. 32 …”