SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells

We have characterized the pancreatic phenotype of mice carrying a gene trap mutation in Sel1l. We show that Sel1l expression in the developing pancreas coincides with differentiation of the endocrine and exocrine lineages. Mice homozygous for the gene trap mutation die prenatally and display an impaired pancreatic epithelial morphology and cell differentiation. The pancreatic epithelial cells of Sel1l mutant embryos are confined to the progenitor cell state throughout the secondary transition. Pharmacological inhibition of Notch signaling partially rescues the pancreatic phenotype of Sel1l mutant embryos.Together, these data suggest that Sel1l is essential for the growth and differentiation of endoderm-derived pancreatic epithelial cells during mouse embryonic development.The multiple cell types that make up the adult pancreas, including endocrine, exocrine and ductal cells, derive from a common pool of pancreatic progenitors. Pancreatic development in mice begins at embryonic day 9.5 (E9.5) with the formation of two epithelial buds on the dorsal and ventral side of the primitive gut endoderm [1]. Epithelial cells within the pancreatic buds proliferate rapidly and branch out during later embryonic days to form a complex tubular network comprised of undifferentiated multipotent progenitor cells [2,3]. Starting at E13.5, the expanded pancreatic epithelial cells undergo an asynchronized wave of differentiation to give rise to all the differentiated cell types of the adult pancreas, including acinar cells that produce hydrolytic digestive enzymes and islet cells that secrete endocrine hormones [4,5]. Pancreatic morphogenesis depends on a complex and yet incompletely characterized network of transcription factors. Significant efforts have been made in the past few years to understand the role of several important transcription factors, including Pdx1 [6,7], Ptf1a [8,9], Sox9 [10,11]9, Ngn3 [12,13], NeuroD1 [14,15], Pax4 [16], Pax6 [17], Nkx2.2 [18], Nkx6.1 [19], Arx [20]