SMAD4: A Critical Regulator of Cardiac Neural Crest Cell Fate and Vascular Smooth Muscle Differentiation

The pharyngeal arch arteries (PAAs) are precursor vessels which remodel into the aortic arch arteries (AAAs) during embryonic cardiovascular development. Cardiac neural crest cells (NCs) populate the PAAs and differentiate into vascular smooth muscle cells (vSMCs), which is critical for successful PAA-to-AAA remodeling. SMAD4, the central mediator of canonical TGFβ signaling, has been implicated in NC-to-vSMC differentiation; however, its distinct roles in vSMC differentiation and NC survival are unclear.

Here, we investigated the role of SMAD4 in cardiac NC differentiation to vSMCs using lineage-specific inducible mouse strains in an attempt to avoid early embryonic lethality and NC cell death. We found that with global SMAD4 loss, its role in smooth muscle differentiation could be uncoupled from its role in the survival of the cardiac NC in vivo . Moreover, we found that SMAD4 may regulate the induction of fibronectin, a known mediator of NC-to-vSMC differentiation. Finally, we found that SMAD4 is required in NCs cell-autonomously for NC-to-vSMC differentiation and for NC contribution to and persistence in the pharyngeal arch mesenchyme.

Overall, this study demonstrates the critical role of SMAD4 in the survival of cardiac NCs, their differentiation to vSMCs, and their contribution to the developing pharyngeal arches.