The coiled-coil domain containing protein Ccdc136b antagonizes maternal Wnt/β-catenin activity during zebrafish...

Area of Science:

• Developmental Biology
• Molecular Biology
• Cancer Research

Background:

• Coiled-coil domain containing protein 136 (CCDC136) is implicated as a tumor suppressor, notably downregulated in gastric and colorectal cancers.
• Its precise biological functions during vertebrate embryonic development remain largely uncharacterized.
• Zebrafish possesses two CCDC136 orthologs, ccdc136a and ccdc136b, with ccdc136b exhibiting high expression during early embryogenesis.

Purpose of the Study:

• To investigate the role of ccdc136b in zebrafish embryonic development.
• To elucidate the molecular mechanism by which ccdc136b influences axial patterning.
• To determine the relationship between ccdc136b, Wnt/β-catenin signaling, and its tumor suppressive function.

Main Methods:

• Morpholino-induced knockdown (morphants) and overexpression of ccdc136b in zebrafish embryos.
• Loss- and gain-of-function studies in mammalian cell lines.
• Analysis of dorsal-ventral axial patterning phenotypes.
• Investigation of interactions with the Wnt/β-catenin pathway components, including APC and β-catenin.

Main Results:

• Zebrafish embryos lacking functional ccdc136b (ccdc136b morphants) exhibit severe dorsalization, indicating a requirement for ccdc136b in establishing the dorsal-ventral axis.
• Ccdc136b functions as a negative regulator of the Wnt/β-catenin signaling pathway.
• CCDC136b interacts with APC, enhancing its binding to β-catenin and promoting β-catenin degradation.

Conclusions:

• CCDC136b is crucial for regulating dorsal-ventral patterning in zebrafish embryos.
• The mechanism involves antagonizing Wnt/β-catenin signaling through interaction with APC and facilitating β-catenin turnover.
• These findings provide insights into CCDC136's role in development and suggest a potential mechanism for its tumor suppressive activity in carcinogenesis.