Study of Gas requirement for pancreatic islet cell development

RODRIGUEZ SEGUÍ, SANTIAGO A; STEFFEN, DANA; TRABA, SILVO A; ROMERO, AGUSTIN; PINKASZ, MARINA; MONTENEGRO, MAURICIO; GUTKIND, J SILVIO

Bariloche

Simposio; The Fourth South American Spring Symposium in Signal Transduction and Molecular Medicine (SISTAM 2018); 2018

We have previously reported the construction of genomic cis regulatory maps in human embryonic pancreas of 6-7 wpc and in vitro pancreatic progenitor cells derived from human pluripotent stem cells. Analysis of these epigenomic maps led to the discovery that TEAD and YAP are important gene expression regulators in the embryonic pancreas. In more detail, we found that the nuclear localization of the coactivator YAP is important for maintaining the phenotype of pancreatic multipotent progenitor cells, while downregulation of this factor is seen in endocrine commited cells. To date, it is not clear which upstream signaling cues, acting during normal pancreas development, cause the downregulation of YAP and its regulated gene network that might ultimately allow endocrine commitment. Our preliminary results suggest that a subset of the genes preferentially active in pancreatic progenitor cells could be inhibited by the G protein-coupled receptor (GPCR) signaling network. This signaling network could be interacting with the mechanisms controled by TEAD and YAP during β cell development, similarly to what was recently reported in folicullar epithelial cells. Here, we used transgenic mice to allow for the conditional deletion of the Gnas gene (coding for the Gαs protein) in the pancreas. Our preliminary results suggest that these mice present a metabolic defect (associated with lower weight) due to an alteration in pancreatic islet cell composition.