Custos controls β-catenin to regulate head development during vertebrate embryogenesis

Area of Science:

• Developmental Biology
• Molecular Biology
• Cell Signaling

Background:

• Precise canonical Wnt pathway control is vital for embryogenesis and health.
• Wnt pathway dysregulation is linked to diseases like cancer and birth defects.
• The mechanism of beta-catenin cytoplasmic to nuclear translocation in Wnt signaling is not fully understood.

Purpose of the Study:

• To identify and characterize novel components of the canonical Wnt signaling pathway.
• To investigate the role of the newly identified protein, Custos, in Wnt signaling and embryonic development.
• To elucidate the mechanism by which Custos regulates beta-catenin translocation and Wnt pathway activity.

Main Methods:

• Identification of Custos as a Dishevelled-interacting protein.
• Analysis of Custos expression patterns in Xenopus embryos.
• Functional studies (depletion and overexpression) in Xenopus and zebrafish to assess effects on development and Wnt signaling.
• Biochemical assays to determine Custos interaction with beta-catenin and its effect on translocation.

Main Results:

• Custos, a novel Dishevelled-interacting protein, was identified.
• Custos depletion or overexpression in Xenopus disrupted anterior head formation and Spemann-Mangold organizer development.
• Custos inhibited Wnt pathway activity by modulating beta-catenin nuclear import, not stability, affecting secondary axis induction and TCF-dependent transcription.
• Conserved function of Custos in anterior head development was confirmed in zebrafish.

Conclusions:

• Custos is a novel regulator of canonical Wnt signaling, fine-tuning beta-catenin nuclear translocation.
• Custos plays a crucial role in embryonic head development.
• Custos adds a new layer of regulatory control to the Wnt-beta-catenin signaling cascade.