Hedgehog signalling controls sinoatrial node development and atrioventricular cushion formation

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Genetics

Background:

• The hedgehog pathway, mediated by the Smoothened receptor, plays vital roles in embryonic development.
• The specific functions of Smoothened in cardiac development, particularly in the formation of the sinoatrial node and heart valves, are not fully elucidated.

Purpose of the Study:

• To investigate the role of Smoothened in cardiac development, focusing on its impact on the venous pole, sinoatrial node, and endocardial-to-mesenchymal transition.
• To identify molecular pathways regulated by Smoothened involved in cardiac progenitor cell commitment.

Main Methods:

• Conditional knockout of Smoothened in mesodermal cells.
• Cardiac cell culture and explant assays.
• Gene expression analysis (scRNAseq, RNAseq) and signaling pathway investigation (Bmp signaling).

Main Results:

• Smoothened deficiency in mesoderm impairs venous pole development, leading to atrial/inflow tract hypoplasia and bradycardia.
• Reduced expression of sinoatrial node development genes and failed endocardial-to-mesenchymal transition in the atrioventricular cushion were observed.
• A Gli2-Tbx5-Hcn4 pathway regulating sinoatrial node development was identified, and Bmp2 was found to rescue endocardial-to-mesenchymal transition defects.

Conclusions:

• Smoothened-mediated hedgehog signaling is essential for posterior cardiac progenitor commitment.
• Disruption of this pathway affects cardiac conduction system and heart valve development, suggesting a role in congenital heart disease etiology.