Mesodermal expression of integrin α5β1 regulates neural crest development and cardiovascular morphogenesis

Abstract

Integrin α5-null embryos die in mid-gestation from severe defects in cardiovascular morphogenesis, which stem from defective development of the neural crest, heart and vasculature. To investigate the role of integrin α5β1 in cardiovascular development, we used the Mesp1Cre knock-in strain of mice to ablate integrin α5 in the anterior mesoderm, which gives rise to all of the cardiac and many of the vascular and muscle lineages in the anterior portion of the embryo. Surprisingly, we found that mutant embryos displayed numerous defects related to the abnormal development of the neural crest such as cleft palate, ventricular septal defect, abnormal development of hypoglossal nerves, and defective remodeling of the aortic arch arteries. We found that defects in arch artery remodeling stem from the role of mesodermal integrin α5β1 in neural crest proliferation and differentiation into vascular smooth muscle cells, while proliferation of pharyngeal mesoderm and differentiation of mesodermal derivatives into vascular smooth muscle cells was not defective. Taken together our studies demonstrate a requisite role for mesodermal integrin α5β1 in signaling between the mesoderm and the neural crest, thereby regulating neural crest-dependent morphogenesis of essential embryonic structures.

Endothelium in the pharyngeal arches 3, 4 and 6 is derived from the second heart field

“…To complement these experiments and to identify the major source of endothelial cells in the PAAs 3 – 6, we used lineage tracing. Our earlier studies and the work of others showed that the majority of PAA endothelial cells in mice are derived from Mesp1 + precursors (Liang et al, 2014; Papangeli and Scambler, 2013). We also found that the majority of PAA endothelial cells express Isl1 in embryos older than 36s (Chen et al, 2015), suggesting that PAA endothelial cells could have been derived from the second heart field (SHF) mesoderm.…”

“…Broadly, the anterior mesoderm, which includes the PAA endothelium arises from Mesp1 -expressing progenitors during early gastrulation (Liang et al, 2014; Papangeli and Scambler, 2013). It is also known that a small proportion of the PAA endothelium expresses Nkx2.5 or derives from Nkx2.5-expressing progenitors (Paffett-Lugassy et al, 2013).…”

Collaboration of fibronectin matrix with other extracellular signals in morphogenesis and differentiation

“…Differentiation of cardiac neural crest into vascular smooth muscle cells (VSMCs) was affected by the absence of this integrin in mesodermal cells which caused morphogenetic defects in aortic arch arteries [16]**. These results suggest a model in which the ECM assembled by α5β1 on mesodermal cells influences neural crest-derived cells to develop into VSMCs.…”

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

“…Histology, immunohistochemistry and β-gal staining were performed as described previously (Chen et al, 2015;Liang et al, 2014). For more details about the procedures and antibodies, see supplementary Materials and Methods.…”