According to the lateral inhibition model, during early pancreas development, Neurog3 expression in multipotent progenitor cells (MPCs) initiates endocrine differentiation and activates expression of the Notch ligand Dll1. Dll1 then activates Notch receptors in neighbouring cells, which turns on Hes1 expression. Finally, Hes1 inhibits Neurog3 expression in these neighbouring cells, thereby preventing excessive endocrine differentiation. On , Palle Serup and colleagues challenge this model by showing that Dll1, Hes1 and Dll1/Hes1 mutant phenotypes diverge at key points of mouse pancreas development. Moreover, pancreatic hypoplasia in Dll1 mutants is independent of endocrine development and is not, therefore, caused by excessive endocrine differentiation and progenitor depletion, as previously believed. Instead, the researchers report, reduced MPC proliferation is responsible for this hypoplasia. Other results indicate that Ptf1a (pancreas transcription factor 1 subunit α) activates Dll1 expression and that Hes1 sustains Ptf1a expression and Dll1 expression in early MPCs. Thus, Ptf1a-mediated control of Dll1 expression, rather than a lateral inhibition mechanism, is crucial for Notch-mediated control of early pancreas development.
