Neurog3-dependent pancreas dysgenesis causes ectopic pancreas in Hes1 mutants

Abstract

Mutations in Hes1, a target gene of the Notch signalling pathway, lead to ectopic pancreas by a poorly described mechanism. Here we use genetic inactivation of Hes1 combined with lineage tracing and live-imaging to reveal an endodermal requirement for Hes1 and show that ectopic pancreas tissue is derived from the dorsal pancreas primordium. RNA-seq analysis of sorted E10.5 Hes1+/+ and Hes1−/− Pdx1-GFP+ cells suggested that upregulation of endocrine lineage genes in Hes1−/− embryos was the major defect and accordingly early pancreas morphogenesis was normalised, and the ectopic pancreas phenotype suppressed, in Hes1−/−Neurog3−/− embryos. In Mib1 mutants we found a near total depletion of dorsal progenitors, which was replaced by an anterior Gcg+ extension. Together, our results demonstrate that aberrant morphogenesis is the cause of ectopic pancreas and that a part of the endocrine differentiation program is mechanistically involved in the dysgenesis. Our results suggest that the ratio of endocrine lineage to progenitor cells is important for morphogenesis and that a strong endocrinogenic phenotype without complete progenitor depletion as seen in Hes1 mutants provokes an extreme dysgenesis that causes ectopic pancreas.