WDR5 regulates left-right patterning via chromatin-dependent and -independent functions

Area of Science:

• Developmental Biology
• Genetics
• Molecular Biology

Background:

• Congenital heart disease (CHD) is a leading cause of infant mortality, with genetic underpinnings often unclear.
• Heterotaxy, a disorder of left-right (LR) patterning, is associated with CHD, suggesting a role for LR patterning genes in cardiac development.
• The chromatin modifier WDR5, known for its role in H3K4 methylation, has an uncharacterized function in LR patterning.

Purpose of the Study:

• To investigate the role of WDR5 in left-right (LR) patterning and its potential link to congenital heart disease (CHD).
• To elucidate the molecular mechanisms by which WDR5 influences LR patterning and ciliogenesis.

Main Methods:

• Utilized *Xenopus* models to study the effects of Wdr5 depletion on LR patterning and ciliogenesis.
• Investigated WDR5 expression patterns in monociliated cells of the LR organizer (LRO).
• Assessed the impact of *foxj1* expression and a mutant WDR5 form on LR patterning defects.

Main Results:

• Wdr5 depletion in *Xenopus* embryos resulted in significant LR patterning defects, linked to impaired ciliogenesis.
• WDR5 was found to be crucial for regulating *foxj1* expression in the LRO, and its addition partially rescued LR defects.
• WDR5 demonstrated a dual role, with nuclear localization affecting *foxj1* and a separate, H3K4-independent function at the base of cilia.

Conclusions:

• WDR5 plays a critical, multifaceted role in embryonic left-right patterning, impacting both ciliogenesis and gene regulation.
• These findings provide novel insights into the genetic etiology of heterotaxy and CHD, highlighting WDR5 as a key player.
• The study identifies WDR5 as a potential therapeutic target for ciliopathies and related congenital disorders.