Canonical Wnt pathway modulation is required to correctly execute multiple independent cellular dynamic programs...

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Cranial neural tube closure defects are common and severe birth defects.
• Wnt signaling pathway mutations, like LRP6 loss, cause these defects, but cellular mechanisms are unclear.

Purpose of the Study:

• To investigate the role of Wnt signaling dynamics in cranial neural tube closure using mouse models.
• To examine effects of Wnt pathway reduction and hyperactivation on neural fold development.

Main Methods:

• Utilized LRP6 mutant mice for global and conditional Wnt signaling reduction.
• Employed APC conditional inactivation mutants to study Wnt pathway hyperactivation.
• Analyzed cell proliferation, cell shape change, and actin organization during closure.

Main Results:

• Global Wnt reduction caused cranial neural fold hyperplasia due to excessive proliferation, blocking closure.
• Wnt hyperactivation at later stages disrupted actin organization, inhibiting apical constriction and neural fold elevation.
• Wnt signaling regulates distinct cellular events at different stages of cranial closure.

Conclusions:

• Wnt signaling must be precisely modulated to restrict early cell proliferation and promote later apical constriction for effective cranial neural tube closure.
• Dysregulation of Wnt signaling leads to distinct defects at different developmental stages.