Serafimidis, I., Heximer, S., Beis, D., and Gavalas, A. (2011) GPCR signaling and S1P play a phylogenetically conserved role in endocrine pancreas morphogenesis. Molecular and cellular biology. 31(22):4442-53.
During development pancreatic endocrine cells migrate in a coordinated fashion. This migration is necessary to form fully functional islets but the mechanisms involved remain unknown. Therapeutic strategies to restore β cell mass and islet functionality by reprogramming endogenous exocrine cells would be strengthened from simultaneous treatments that enhance endocrine cell clustering. We found that endocrine progenitors respond to and regulate G-Protein Coupled Receptor (GPCR) signaling in order to cluster in islets. Rgs4, a dedicated regulator of GPCR signaling, was specifically expressed in early epithelial endocrine progenitors of both zebrafish and mouse and its expression in the mouse endocrine progenitors was strictly dependent upon Ngn3, the key specification gene of the endocrine lineage in the mouse. Rgs4 loss of function resulted in defects in islet cell aggregation. By genetically inactivating Gαi mediated GPCR signaling in endocrine progenitors we established its role in islet cell aggregation in both mouse and zebrafish. Finally, we identified sphingosine-1-phosphate (S1P) as a ligand mediating islet cell aggregation in both species acting through distinct but closely related receptors.