Gene expression, development and disease - CNRS FRE2850  

  MEMBERSDr BARRA Jacqueline / Dr D’ANGELO Anna / Dr FISCHER Evelyne / Mr GARBAY Serge

  Annual Report


Morphogenesis, cell growth and differentiation are key events that are largely controlled by complex tanscriptional circuitries. In this context, transcription factors play a crucial role. The analysis of their function offers a unique perspective for understanding complex biological processes. Our studies focus on a small family of transcription factors called Hepatocyte Nuclear Factor 1αand β (HNF1α and HFN1β. Heterozygous mutations are found in patients suffering from Maturity Onset Diabetes of the Young (MODY3 and 5, respectively). These patients also have renal dysfunctions (MODY3) or kidney developmental defects and cysts (MODY5). These homeoproteins are expressed in epithelia of liver, kidney, pancreas and digestive tract. Our studies have shown that these proteins play seminal roles in morphogenesis, differentiation and physiology of epithelia.

HNF1α or βloss of function.

Inactivation of HNF1α in the mouse results in diabetes mellitus, phenylketonuria and renal Fanconi syndrome. In contrast, germ-line HFN1β-deficiency causes early (E6.5) embryonic lethality. Selective epiblast-specific HNF1βinactivation results in morphogenesis defects in the liver, kidney, pancreas and intestine. The molecular mechanism of these defects is currently being investigated. Tissue-specific inactivation of HNF1βin developing liver results in biliary duct agenesis, whereas in kidney HNF1β inactivation gives rise to Polycystic Kidney Disease (PKD). This phenotype is due to the defective expression of several PKD genes. We have shown that cyst development is linked to a defective Planar Cell Polarization (PCP) of renal tubular cells. We

demonstrated that tubular elongation, during nephron development, is linked to the mitotic alignment of dividing cells with the tubular axis. This pattern is lost in PKD, leading to tubular dilation. The molecular and cellular mechanisms at the basis of these defects are investigated by focusing on the role played by the solitary cilium in the set up of PCP.

In order to gain a better insight on the function played by these two transcription factors we defined a genome-wide map of HFN1 binding sites conserved across different species by an in silico approach. This map is used to identify the direct target genes that are crucially involved in the observed phenotypes.

The phenotypes that we observed in bile ducts, kidney and intestine suggest that HNF1s are key regulators of epithelial tubular structure formation and/or elongation. Unraveling the genetic networks that are controlled by these homeoproteins will help to understand the morphogenesis and differentiation of these structures and their developmental defects.

Our studies should shed light on the molecular and cellular mechanisms of important human diseases.


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Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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