Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development.

Autor: Xu X; The Niels Bohr Institute, University of Copenhagen, DK-2100, Copenhagen Ø, Denmark., Seymour PA; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, DK-2200, Copenhagen N, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen, DK-2200, Copenhagen N, Denmark., Sneppen K; The Niels Bohr Institute, University of Copenhagen, DK-2100, Copenhagen Ø, Denmark., Trusina A; The Niels Bohr Institute, University of Copenhagen, DK-2100, Copenhagen Ø, Denmark., Egeskov-Madsen AR; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, DK-2200, Copenhagen N, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen, DK-2200, Copenhagen N, Denmark., Jørgensen MC; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, DK-2200, Copenhagen N, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen, DK-2200, Copenhagen N, Denmark., Jensen MH; The Niels Bohr Institute, University of Copenhagen, DK-2100, Copenhagen Ø, Denmark. mhjensen@nbi.ku.dk., Serup P; Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, DK-2200, Copenhagen N, Denmark. palle.serup@sund.ku.dk.; Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen, DK-2200, Copenhagen N, Denmark. palle.serup@sund.ku.dk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jan 21; Vol. 14 (1), pp. 348. Date of Electronic Publication: 2023 Jan 21.
DOI: 10.1038/s41467-023-35963-w
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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