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Differentiation of epithelial cells

Team leader : Marco PONTOGLIO

 

Tinkering during evolution has adapted a limited number of signalling pathways to a large number of diverse developmental processes. In this respect, transcription factors, via their concerted action, promote the temporal and spatial expression of key signalling molecules and mediators.

We try to understand the molecular and cellular mechanisms of these phenomena via the study of the function played by a small family of transcription factors, Hepatocyte Nuclear Factor 1 alpha and beta. These proteins are selectively expressed in polarized epithelia of liver, kidney, pancreas and digestive tract. HNF1 alpha and beta deficiency are responsible for important human pathologies including cystic kidney, renal hypodysplasia and type 2 diabetes mellitus.

By using mouse model studies, we have shown that these proteins play seminal roles in the genetic programs responsible for the morphogenesis and differentiation of several epithelia. In particular, we have shown that these factors control crucial aspects of morphogenesis involving tissue polarity and differentiation.

However, the molecular and cellular mechanisms of their action and their link to signalling cascades remain largely unknown. With a multidisciplinary and integrated approaches that includes Genomics and Bioinformatics, Molecular Biology, Cell Biology and Genetics we should obtain deep insights into the mechanisms of epithelial specific developmental events.

In particular, the major objectives of this research project will be to:

(1) Understand the molecular mechanisms of target gene activation by HNF1alpha and beta.

(2) Identify the functions played by HNF1alpha and beta in kidney development and disease.

(3) Unravel the interconnection between cilia, tissue polarity and Polycystic Kidney Disease.

(4) Identify modifier loci controlling the diabetic phenotype triggered by HNF1alpha deficiency.

In conclusion, this research project should help understanding some of the most intriguing cellular and developmental processes whose dysfunction is at the basis of important human diseases.

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