Hepatocyte nuclear factor 1β controls nephron tubular development

Abstract

SUMMARYNephron morphogenesis is a complex process that generates blood-filtration units (glomeruli) connected to extremely long and patterned tubular structures. Hepatocyte nuclear factor 1β (HNF1β) is a divergent homeobox transcription factor that is expressed in kidney from the first steps of nephrogenesis. Mutations in HNF1B (OMIM #137920) are frequently found in patients with developmental renal pathologies, the mechanisms of which have not been completely elucidated. Here we show that inactivation of Hnf1b in the murine metanephric mesenchyme leads to a drastic tubular defect characterized by the absence of proximal, distal and Henle's loop segments. Nephrons were eventually characterized by glomeruli, with a dilated urinary space, directly connected to collecting ducts via a primitive and short tubule. In the absence of HNF1β early nephron precursors gave rise to deformed S-shaped bodies characterized by the absence of the typical bulge of epithelial cells at the bend between the mid and lower segments. The lack of this bulge eventually led to the absence of proximal tubules and Henle's loops. The expression of several genes, including Irx1, Osr2 and Pou3f3, was downregulated in the S-shaped bodies. We also observed decreased expression of Dll1 and the consequent defective activation of Notch in the prospective tubular compartment of comma-and S-shaped bodies. Our results reveal a novel hierarchical relationship between HNF1β and key genes involved in renal development. In addition, these studies define a novel structural and functional component of S-shaped bodies at the origin of tubule formation.

HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2

“…Thus, our data represent not only a significant advance in comprehension of the regulatory networks controlling the early steps of nephron segmentation but might also provide deeper insights into the complex RCAD disease associated with heterozygous mutations in HNF1B. Remarkably, conditional inactivation of Hnf1b in nephron progenitors using the Six2-cre line and another Hnf1b floxed allele resulted in the same phenotype described here, further confirming the crucial role of HNF1B in nephron patterning (Massa et al, 2013).…”

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

“…A direct regulation of Dll1 by Hnf1b, as recently shown in the kidney (Heliot et al, 2013;Massa et al, 2013), does not seem to occur in the pancreas, as ChIP on E12.5 pancreata showed no Hnf1b recruitment to a conserved region of Dll1 (data not shown). Recent data suggested a role for Dll1, which is activated by Ptf1a, in MPC proliferation (Ahnfelt-Ronne et al, 2012).…”

Magnesium in Man: Implications for Health and Disease

“…Renal cysts and diabetes syndrome (RCAD; OMIM 137920) is caused by mutations in hepatocyte nuclear factor 1␤ (HNF1␤) and consists of a heterogeneous group of symptoms including renal cysts (Ϯ70% of patients), maturity onset diabetes of the young subtype 5 (MODY5; Ϯ50%), and hypomagnesemia (Ϯ45%) (11,82). HNF1␤ is a transcription factor regulating gene expression in kidney development (331). FXYD2b expression is one of several genes that is regulated by HNF1␤ (155), which may explain its role in renal Mg 2ϩ handling.…”