From dynamic expression patterns to boundary formation in the presomitic mesoderm.

Area of Science:

• Developmental Biology
• Computational Biology
• Genetics

Background:

• Vertebrate body segmentation initiates during embryogenesis via signaling gradients and gene oscillations in the presomitic mesoderm (PSM).
• Existing computational models often address only partial aspects of somitogenesis, lacking a complete causal chain simulation from gene expression to segmentation.
• Simulating the entire process, from gene regulation in the growth zone through cell interactions to segmentation, remains a challenge.

Purpose of the Study:

• To develop an enhanced computational model of mouse somitogenesis that simulates the complete causal chain from gene expression to segmentation.
• To integrate gradient formation (WNT3A, FGF8), periodic gene expression, and Delta/Notch signaling within a virtual cell-based model of the PSM.
• To investigate the role of Hes7 as the core oscillator and LFNG as a modulator in the somitogenesis clock.

Main Methods:

• Development of an enhanced gene regulatory network (GRN) model for mice within a simulation program.
• Modeling the presomitic mesoderm (PSM) using numerous virtual cells to simulate growth and interactions.
• Integration of WNT3A and FGF8 gradient formation, periodic gene expression patterns, and Delta/Notch signaling dynamics.

Main Results:

• The model successfully simulates the formation of WNT3A and FGF8 gradients and periodic gene expression, including oscillating Dll1 expression driven by Hes7-Dll1 negative feedback.
• The simulation reproduces the experimentally observed wave of activated NOTCH (NICD) resulting from GRN interactions.
• The model demonstrates robustness across various parameter values, with Hes7 mRNA and protein decay significantly influencing the core oscillator. It also predicts interference between Hes1 and Hes7 oscillators.

Conclusions:

• A comprehensive computational model of mouse somitogenesis has been successfully developed, with Hes7 identified as the core oscillator.
• The model accurately reproduces numerous experimentally observed phenomena in somitogenesis, validating its predictive power.
• The study provides insights into the complex interplay of signaling pathways and gene regulatory networks governing vertebrate body segmentation.