Highlights d Ultradian Dll1 and Hes1 oscillations are crucial for the growth of pancreas progenitors d Hes1 oscillation parameters are associated with the bipotent versus pro-acinar fate choice d Jag1 attenuates growth and specifies bipotent ductendocrine progenitors d Cellular context determines whether Jag1 inhibits or activates Notch
Pancreatic β-cells arise from bipotent trunk progenitors (TrPCs) that are specified from multipotent pancreatic progenitors (MPCs) in a Notch-dependent manner. The time window during which Notch signaling is required to specify TrPCs and the identity of the Notch ligands required for this patterning process remain obscure. Here we show that blocking Notch signal transduction before E13 drives progenitors to an acinar fate while blockade after E13 results in amplified and accelerated endocrine differentiation. Mapping of Dll1 and Jag1 expression using IF and novel targeted reporters revealed that uniform Jag1 expression in E10.
The Notch ligands Jag1 and Dll1 guide differentiation of multipotent pancreatic progenitor cells (MPCs) into unipotent pro-acinar cells (PACs) and bipotent duct/endocrine progenitors (BPs). Ligand-mediated trans-activation of Notch receptors induces oscillating expression of the transcription factor Hes1, while ligand-receptor cis-interaction indirectly represses Hes1 activation. Despite Dll1 and Jag1 both displaying cis- and trans-interactions, the two mutants have different phenotypes for reasons not fully understood. Here, we present a mathematical model that recapitulates the spatiotemporal differentiation of MPCs into PACs and BPs. The model correctly captures cell fate changes in Notch pathway knockout mice and small molecule inhibitor studies, and a requirement for oscillatory Hes1 expression to maintain the multipotent state. Crucially, the model entails cell-autonomous attenuation of Notch signaling by Jag1-mediated cis-inhibition in MPC differentiation. The model sheds light on the underlying mechanisms, suggesting that cis-interaction is crucial for exiting the multipotent state, while trans-interaction is required for adopting the bipotent fate.
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