NOTCH activation interferes with cell fate specification in the gastrulating mouse embryo

Area of Science:

• Developmental Biology
• Cell Signaling Pathways
• Genetics and Genomics

Background:

• NOTCH signalling is crucial for cell fate determination during development.
• Canonical RBPJ-dependent NOTCH signalling influences lineage commitment in mouse embryonic stem cells (ESCs).
• NOTCH activation in ESCs promotes neural fate, while suppression favors cardiomyocyte differentiation.

Purpose of the Study:

• To investigate the in vivo role of NOTCH signalling in cell fate specification during mammalian gastrulation.
• To elucidate the mechanisms by which NOTCH signalling shapes embryonic development.
• To understand the interplay between NOTCH and NODAL signalling in early patterning.

Main Methods:

• Genetic approaches to constitutively activate the NOTCH pathway in mouse embryos.
• Analysis of embryonic development, including anterior-posterior polarity and gastrulation.
• Assessment of RBPJ-deficient backgrounds for rescue experiments.
• Epiblast-specific NOTCH activation studies.
• Investigation of NODAL signalling misregulation.

Main Results:

• Constitutive NOTCH activation does not perturb early embryonic development or anterior-posterior polarity.
• Widespread NOTCH activity in the epiblast causes significant gastrulation defects, fully rescued in RBPJ-deficient embryos.
• Epiblast-specific NOTCH activation leads to neurectoderm identity acquisition and disrupts anterior primitive streak derivatives (mouse organiser).
• Forced NOTCH activation results in misregulation of NODAL signalling.

Conclusions:

• Canonical NOTCH signalling plays a previously unidentified role during mammalian gastrulation.
• NOTCH signalling influences cell fate specification by promoting neurectoderm identity and affecting mesodermal development.
• The study provides insights into cell fate mechanisms during in vivo development and in vitro differentiation.