Hnf1b haploinsufficiency differentially affects developmental target genes in a new renal cysts and diabetes mouse model

Disease Models & Mechanisms

Martin Reczko¹  Petra Zürbig²  Pedro Magalhães²  Leticia L. Niborski³  Silvia Cereghini³  Celine Lesaulnier³  Mélanie Paces-Fessy³  Pierbruno Ricci³  Maria Kuzma-Kuzniarska³  Edwige Declercq³  Adeline Bourgeois³  Muriel Umbhauer³  Alain Doucet⁴ 

[1] Biomedical Sciences Research Center Alexander Fleming, Institute for Fundamental Biomedical Science, 16672 Athens, Greece;Mosaiques Diagnostics, 30659 Hannover, Germany;Sorbonne Université, CNRS, Institut de Biologie Paris Seine, Laboratoire de Biologie du Développement, IBPS, UMR7622, F-75005 Paris, France;Sorbonne Université, Université Paris Descartes, UMRS 1138, CNRS, ERL 8228, Centre de Recherche des Cordeliers, F-75006 Paris, France;

关键词: hnf1b transcription factor;    rcad syndrome;    gene dosage;    glomerular and proximal tubule cysts;    mouse models;    transcriptomics;   

DOI  :  10.1242/dmm.047498

来源: DOAJ

【 摘 要 】

Heterozygous mutations in HNF1B cause the complex syndrome renal cysts and diabetes (RCAD), characterized by developmental abnormalities of the kidneys, genital tracts and pancreas, and a variety of renal, pancreas and liver dysfunctions. The pathogenesis underlying this syndrome remains unclear as mice with heterozygous null mutations have no phenotype, while constitutive/conditional Hnf1b ablation leads to more severe phenotypes. We generated a novel mouse model carrying an identified human mutation at the intron-2 splice donor site. Unlike heterozygous mice previously characterized, mice heterozygous for the splicing mutation exhibited decreased HNF1B protein levels and bilateral renal cysts from embryonic day 15, originated from glomeruli, early proximal tubules (PTs) and intermediate nephron segments, concurrently with delayed PT differentiation, hydronephrosis and rare genital tract anomalies. Consistently, mRNA sequencing showed that most downregulated genes in embryonic kidneys were primarily expressed in early PTs and the loop of Henle and involved in ion/drug transport, organic acid and lipid metabolic processes, while the expression of previously identified targets upon Hnf1b ablation, including cystic disease genes, was weakly or not affected. Postnatal analyses revealed renal abnormalities, ranging from glomerular cysts to hydronephrosis and, rarely, multicystic dysplasia. Urinary proteomics uncovered a particular profile predictive of progressive decline in kidney function and fibrosis, and displayed common features with a recently reported urine proteome in an RCAD pediatric cohort. Altogether, our results show that reduced HNF1B levels lead to developmental disease phenotypes associated with the deregulation of a subset of HNF1B targets. They further suggest that this model represents a unique clinical/pathological viable model of the RCAD disease.

【 授权许可】

Unknown