Wdr68 Mediates Dorsal and Ventral Patterning Events for Craniofacial Development

Area of Science:

• Developmental Biology
• Genetics
• Craniofacial Development

Background:

• Birth defects significantly contribute to infant mortality and long-term disability.
• Craniofacial syndromes often arise from defects in signaling pathways governing cranial neural crest cell (CNCC) development.
• Bone Morphogenetic Protein (BMP), Endothelin-1 (Edn1), and Jagged-Notch signaling pathways are critical for craniofacial patterning and interact in a complex hierarchy.

Purpose of the Study:

• To investigate the role of the scaffolding protein Wdr68 in craniofacial development and its relationship with BMP, Edn1, and Jag1b signaling.
• To determine the stage-specific requirement for Wdr68 activity and its downstream targets.
• To explore the interplay between TGF-β signaling and BMP signaling in Wdr68-deficient craniofacial development.

Main Methods:

• Utilized zebrafish as a model organism to study craniofacial development.
• Generated and analyzed wdr68 mutant zebrafish embryos.
• Administered BMP agonist (isoliquiritigenin, ISL) and TGF-β signaling inhibitor (SB431542) to assess rescue effects on gene expression and craniofacial morphology.

Main Results:

• Wdr68 activity is essential between the 17-somites and prim-5 stages for craniofacial development.
• Wdr68 regulates Edn1 expression, which in turn influences Jag1b, hey1, and grem2 expression in CNCCs.
• TGF-β signaling interferes with BMP signaling, and this interference is exacerbated in wdr68 mutant cells; SB431542 treatment partially rescued Edn1 and dlx2a expression and craniofacial defects in wdr68 mutants.

Conclusions:

• Wdr68 plays an indirect but critical role in the BMP-Edn1-Jag1b signaling cascade, essential for proper craniofacial patterning.
• Wdr68 is required for the correct dorso-anterior expression of dlx1a and dlx2a in CNCCs.
• Inhibition of TGF-β signaling can partially rescue craniofacial defects in wdr68 mutants, highlighting its role in modulating BMP signaling.