WDR1-regulated actin dynamics is required for outflow tract and right ventricle development

Area of Science:

• Developmental Biology
• Cardiovascular Research
• Cellular Biology

Background:

• Congenital heart defects, particularly outflow tract (OFT) anomalies, represent a significant portion of birth defects.
• The second heart field (SHF) is critical for OFT and right ventricle (RV) development, but the underlying mechanisms are not fully understood.
• WD-repeat domain 1 (WDR1), a co-factor of actin depolymerizing factor/cofilin, plays a role in actin dynamics, but its function in embryonic heart development was unknown.

Purpose of the Study:

• To investigate the role of WDR1 in the development of the OFT and RV.
• To elucidate the cellular and molecular mechanisms by which WDR1 influences embryonic heart formation.

Main Methods:

• Generation of Wdr1-deficient mouse models: Wdr1 floxed mice with Nkx2.5-Cre for global embryonic heart deletion and SHF progenitors-specific Wdr1 deletion (shfKO) mice.
• Analysis of embryonic lethality, OFT and RV morphology, SHF cell deployment, proliferation, and cardiomyocyte organization.
• Examination of myofibrillar assembly and spatial arrangement of cardiomyocytes in developing hearts.

Main Results:

• Wdr1 deletion in the embryonic heart (Wdr1^F/F;Nkx2.5-Cre) resulted in embryonic lethality and hypoplasia of the OFT and RV.
• SHF-specific Wdr1 deletion (shfKO) led to embryonic lethality by E11.5 and reduced OFT and RV size at E10.5.
• While cell number and proliferation were unaffected in shfKO embryos, cardiomyocyte organization and myofibrillar assembly were severely disrupted, with cells dissociating and arranging disorderly.

Conclusions:

• WDR1 is essential for normal OFT and RV development in embryonic hearts.
• WDR1-mediated actin dynamics are critical for controlling the size of the OFT and RV, likely by regulating cardiomyocyte spatial organization.