Abstract
In type-1 diabetic patients glucose homeostasis is regulated by frequent injections of insulin. Beta cell mass can be restored by islet transplantation, but lack of organ donors and the requirement for immunosuppressants make this approach problematic. Recent developments in protocols to differentiate embryonic stem cells to beta cells provide hope for a renewable source of transplantable beta cells. In vertebrates Pdx1-expressing endoderm cells give rise to endocrine and exocrine cell lineages. In previous work we established that development of all pancreatic lineages requires retinoic acid (RA) signaling upstream of Pdx1. However, the gene regulatory network that leads to endocrine pancreas specification downstream of RA signaling is not well characterized. Using an unbiased microarray approach we identified Mnx1 (Hb9) as a RA regulated endoderm transcription factor. By combining manipulation of gene function with transgenic reporter analysis we establish a critical role for Mnx1 in controlling cell fate decisions within the endocrine pancreas progenitor lineage. Previous studies in both zebrafish and mouse have revealed that Mnx1 plays a role in beta cell development. Here, we show that RA signaling regulates the expression of mnx1 in the endoderm, and that mnx1 functions downstream of RA signaling to establish beta cell fate. Published work has shown that morpholino-mediated knock down of zebrafish mnx1 decreases beta cell number. We now demonstrate that in Mnx1-deficient embryos beta cell precursors fail to express insulin and convert to glucagon expressing alpha cells. In summary, we propose that mnx1 functions downstream of RA signaling in the endocrine progenitors to promote beta cell fate.