SMAD4: A critical regulator of cardiac neural crest cell fate and vascular smooth muscle development

During embryogenesis, cardiac neural crest-derived cells (NCs) migrate into the pharyngeal arches and give rise to the vascular smooth muscle cells (vSMCs) of the pharyngeal arch arteries (PAAs). vSMCs are critical for the remodeling of the PAAs into their final adult configuration, giving rise to the aortic arch and its arteries (AAAs).

We investigated the role of SMAD4 in NC-to-vSMC differentiation using lineage-specific inducible mouse strains. We found that the expression of SMAD4 in the NC is indelible for regulating the survival of cardiac NCs. Although the ablation of SMAD4 at E9.5 in the NC lineage led to a near-complete absence of NCs in the pharyngeal arches, PAAs became invested with vSMCs derived from a compensatory source. Analysis of AAA development at E16.5 showed that the alternative vSMC source compensated for the lack of NC-derived vSMCs and rescued AAA morphogenesis.

Our studies uncovered the requisite role of SMAD4 in the contribution of the NC to the pharyngeal arch mesenchyme. We found that in the absence of SMAD4⁺ NCs, vSMCs around the PAAs arose from a different progenitor source, rescuing AAA morphogenesis. These findings shed light on the remarkable plasticity of developmental mechanisms governing AAA development.