Retinoic acid signaling within pancreatic endocrine progenitors regulates mouse and human pancreatic islet 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 during the later stages of pancreas development is not well understood. In this study, we generated an inducible system to block RA signaling and demonstrate that disruption of the RA pathway within the Neurog3-expressing endocrine progenitor population is required for appropriate mouse b cell differentiation and repression of critical d 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 determined 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 endocrine cell fate. Overall design: e16.5 pancreas RNA-seq from Neurog3:cre alone (n=3) and Neurog3:cre;RARdnfl/fl (n=3)