Model illustrating the proposed mechanism for regulation of pancreatic beta and alpha cell allocation by apical-basal polarity. Tight junctions (TJs) provide essential physical and signaling cues for establishing apical-basal polarity. Within the polarized EPs, PROM1 facilitates the recruitment of ERM family proteins to bring PKA to membrane lipid rafts where GPCR, AC, and PKA substrates are in close proximity to increase the response of cAMP signals. The resulting increased activity of cAMP/PKA-CREB signaling promotes the expression of EGR1 and further inhibits the expression of ARX, thereby allowing EPs to differentiate into beta cells. In the non-polarized environment, EPs exhibit relatively low activity of cAMP/PKA-CREB signaling, subsequently diminishing EGR1 expression and permitting the expression of ARX. This shift allows EPs to differentiate into alpha cells. FSK and IBMX, as cAMP agonists, can increase intracellular cAMP levels and promote the generation of beta cells. *p< 0.05,**p< 0.01,***p< 0.001 (two-tailed paired Student’s t test). See alsoFigure S6.
