Neurog3-dependent pancreas dysgenesis causes ectopic pancreas in <i>Hes1</i> mutant mice

Abstract

Mutations in <i>Hes1</i>, a target gene of the Notch signalling pathway, lead to ectopic pancreas by a poorly described mechanism. Here, we use genetic inactivation of <i>Hes1</i> 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 <i>Hes1</i>^+/+ and <i>Hes1</i>^-/- Pdx1-GFP⁺ cells suggested that upregulation of endocrine lineage genes in <i>Hes1</i>^-/- embryos was the major defect and, accordingly, early pancreas morphogenesis was normalized, and the ectopic pancreas phenotype suppressed, in <i>Hes1</i>^-/-<i>Neurog3</i>^-/- embryos. In <i>Mib1</i> 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 <i>Hes1</i> mutants, provokes an extreme dysgenesis that causes ectopic pancreas.