Gérard Gradwohl PhD

Course and current status

Gérard Gradwohl (GG) is research director at INSERM. Since 2000 his research group aims at deciphering the gene regulatory cascades controlling endocrine cell differentiation and function in the pancreas and intestine. He earned his PhD in Molecular and Cellular Biology in 1991 at the University Louis Pasteur in Strasbourg (France) in the field of DNA repair. He obtained a permanent position at INSERM in 1991 as research associate. In 1991-1992 he did a postdoc at the Samuel Lunenfeld Research Institute (Mount Sinai Hospital in Toronto Canada) where he studied the role of the receptor tyrosine kinase Tek/tie2 during mouse angiogenesis. He next (1993-2000) identified the Neurogenin/Math4 genes, a novel family of bHLH transcription factors, and studied their function during mouse neurogenesis at the Institute of Genetics and Molecular and Cellular Biology IGBMC (Illkirch, France). After the publication of a seminal study demonstration the key role of Neurogenin3 in the specification of the endocrine fate in the embryonic mouse pancreas he was awarded a starting grant (INSERM Avenir). Gérard Gradwohl is currently group leader at the IGBMC (Illkirch, France) within the Development and Stem Cells Department.

GG is a member of the NIH Beta Cell Biology Consortium (http://www.betacell.org/)

Scientific summary

The main goal of the group is to decipher the molecular and cellular mechanisms controlling the differentiation and function of pancreatic islet cells as well of closely related intestinal endocrine (enteroendocrine) cells. Using mouse genetics and functionnal genomics approaches, we focus on the role of transcription factors in the control of cell fate choices and the acquisition of the generic and specific properties of the different pancreatic endocrine cell types including insulin-secreting beta cells.

Main achievements have been the identification of the transcription factor Neurog3 as the master gene controlling endocrine destiny in pancreatic and intestinal pluripotent progenitors in the mouse embryo. Without Neurog3 mouse islet cells do not develop and mice are diabetic at birth. Next we have identified the Neurog3-regulated genetic program and studied the function of several Neurog3 targets such as Insm1, Pak3, Rfx6 in islet cell maturation and beta cell function.  We also investigate the function Neurog3 and its targets in the adult intestine. We showed that the conditional ablation of Neurog3 in the mouse intestine precludes enteroendocrine cell differentiation.  We explore the pathophysiological consequences of enteroendocrine hormone ablation more particularly in nutrients absorption, glucose metabolism and energy metabolism. Finally we develop mouse models of human diseases recapitulating human mutations found in Neurog3 or its targets.

These studies are relevant both for the development of novel strategies for a stem cell based therapy in diabetes as well as to understand the mechanisms underlying the pathophysiology of pancreatic and enteroendocrine  failure in human patients such as monogenic diabetes or enteric anendocrinosis.

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