Retinoic acid signaling within pancreatic endocrine progenitors regulates mouse and human β cell specification.

Retinoic acid (RA) signaling is essential for multiple developmental processes, including appropriate pancreas formation from the foregut endoderm. RA is also required to generate pancreatic progenitors from human pluripotent stem cells. However, the role of RA signaling during endocrine specification has not been fully explored. In this study, we demonstrate that disruption of RA signaling within the NEUROG3-expressing endocrine progenitor population impairs mouse β cell differentiation and induces ectopic expression of critical δ cell genes, including Somatostatin. In addition, inhibition of the RA pathway in hESC-derived pancreatic progenitors downstream of NEUROG3 induction impairs INSULIN expression. We further determine that RA-regulation of endocrine cell differentiation is mediated through WNT pathway components. Together, these data demonstrate the importance of RA signaling in endocrine specification and identify conserved mechanisms by which RA signaling directs pancreatic endocrine cell fate.