Essential roles of fibronectin in the development of the left–right embryonic body plan

Abstract

Studies in Xenopus laevis suggested that cell-extracellular matrix (ECM) interactions regulate the development of the left-right axis of asymmetry; however, the identities of ECM components and their receptors important for this process have remained unknown. We discovered that FN is required for the establishment of the asymmetric gene expression pattern in early mouse embryos by regulating morphogenesis of the node, while cellular fates of the nodal cells, canonical Wnt and Shh signaling within the node were not perturbed by the absence of FN. FN is also required for the expression of Lefty 1/2 and activation of SMADs 2 and 3 at the floor plate, while cell fate specification of the notochord and the floor plate, as well as signaling within and between these two embryonic organizing centers remained intact in FN-null mutants. Furthermore, our experiments indicate that a major cell surface receptor for FN, integrin α5β1, is also required for the development of the left-right asymmetry, and that this requirement is evolutionarily conserved in fish and mice. Taken together, our studies demonstrate the requisite role for a structural ECM protein and its integrin receptor in the development of the left-right axis of asymmetry in vertebrates.

Shape and position of the node and notochord along the bilateral plane of symmetry are regulated by cell–extracellular matrix interactions

“…Thus defective establishment of the left–right axis in integrin α5-null mutants (Pulina et al, 2011) can be explained by aberrant morphogenesis of the node. Taken together, our studies indicate that integrin α5β1 plays an important role in embryo development by regulating node morphogenesis and the establishment of the left–right body plan.…”

Cilia in vertebrate left–right patterning

“…Loss of the Rho family GTPase Rac1 or the FERM domain protein Lulu/Epb4.1l5 disrupted the movements of ciliated columnar cells with small apical surfaces that must displace larger endoderm cells to reach the ventral surface of the embryo [75]. Mouse embryos with mutations in fibronectin and/or integrin have revealed roles for ECM in establishing normal node morphology and geometry [76,77]. Analyses of endogenous as well as ectopically induced KV in zebrafish embryos have also identified important roles for ECM proteins in positioning ciliated cells [73].…”

The interplay between cell signalling and mechanics in developmental processes

“…Antisense morpholino knockdown and genetic mutations reveal fibronectin is essential to both early development and later organogenesis. For instance, fibronectin is required for Xenopus gastrulation 55,56 as well as zebrafish heart development 57 , endothelial invasion or migration in the developing kidney 58 , and establishment of left-right asymmetry 59 . The requirement of fibronectin during development and its tension-dependent assembly into fibrils make it a key candidate in mechanosensing pathways.…”