Trio cooperates with Myh9 to regulate neural crest-derived craniofacial development

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Trio, a Rho-GEF family member, has three catalytic domains and is vital for cellular processes.
• TRIO mutations are linked to craniofacial abnormalities like mandibular retrusion in humans.
• The precise role of Trio in neural crest cell (NCC)-derived craniofacial development remains unclear.

Purpose of the Study:

• To investigate the molecular mechanisms of Trio in NCC-derived craniofacial development.
• To determine the functional role of Trio in NCC-induced craniofacial abnormalities.

Main Methods:

• Utilized zebrafish and NCC-specific knockout mouse models for in vivo studies.
• Employed iTRAQ, GST pull-down, and proximity ligation assays for in vitro investigations.
• Examined NCC migration, differentiation, and downstream signaling pathways.

Main Results:

• Trio disruption in zebrafish and mice caused NCC migration deficits and impaired differentiation, leading to craniofacial growth deficiency and mandibular retrusion.
• Trio positively regulated Myh9 expression and interacted with Myh9 to co-regulate NCC signaling.
• Disruption of Trio or Myh9 inhibited Rac1 and Cdc42 activity, affecting beta-catenin nuclear export and NCC polarization.
• Craniofacial abnormalities in zebrafish were partially rescued by Myh9, ca-Rac1, or ca-Cdc42 mRNA injection.

Conclusions:

• Trio, primarily interacting with Myh9, is a key regulator of NCC migration and differentiation in craniofacial development.
• Trio deficiency impacts cell polarity and signaling pathways essential for craniofacial growth.
• Zebrafish and mouse models provide valuable systems for studying Trio mutation-related craniofacial abnormalities.