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

Area of Science:

• Developmental Biology
• Cell Signaling
• Mathematical Modeling

Background:

• Notch ligands Jag1 and Dll1 control pancreatic progenitor cell (MPC) differentiation into pro-acinar cells (PACs) and bipotent progenitors (BPs).
• Notch signaling involves both ligand-receptor trans-activation and cis-interactions, influencing Hes1 expression dynamics.
• Distinct phenotypes in Jag1 and Dll1 mutants suggest complex roles for their interactions, not fully understood.

Purpose of the Study:

• To develop a mathematical model of MPC differentiation guided by Notch signaling.
• To elucidate the distinct roles of Jag1 and Dll1 cis- and trans-interactions in cell fate determination.
• To understand the mechanism maintaining the multipotent state and initiating differentiation.

Main Methods:

• Development of a spatiotemporal mathematical model simulating MPC differentiation.
• Validation of the model against experimental data from Notch pathway knockout mice.
• Incorporation of small molecule inhibitor study results to refine model parameters.

Main Results:

• The model accurately recapitulates cell fate changes observed in experimental studies.
• Oscillatory Hes1 expression is identified as crucial for maintaining the multipotent progenitor cell state.
• Jag1-mediated cis-inhibition demonstrates cell-autonomous attenuation of Notch signaling during MPC differentiation.

Conclusions:

• Cis-interaction, particularly by Jag1, is essential for exiting the multipotent progenitor cell state.
• Trans-interaction is required for the adoption of the bipotent progenitor cell fate.
• The model provides mechanistic insights into Notch signaling's role in pancreatic development.