Abstract
The arginine-glycine-aspartate (RGD) motif in fibronectin (FN) represents the major binding site for α5β1 and αvβ3 integrins. Mice lacking a functional RGD motif in FN (FNRGE/RGE) or α5 integrin develop identical phenotypes characterized by embryonic lethality and a severely shortened posterior trunk with kinked neural tubes. Here we show that the FNRGE/RGE embryos arrest both segmentation and axis elongation. The arrest is evident at about E9.0, corresponding to a stage when gastrulation ceases and the tail bud-derived presomitic mesoderm (PSM) induces α5 integrin expression and assumes axis elongation. At this stage cells of the posterior part of the PSM in wild type embryos are tightly coordinated, express somitic oscillator and cyclic genes required for segmentation, and form a tapered tail bud that extends caudally. In contrast, the posterior PSM cells in FNRGE/RGE embryos lost their tight associations, formed a blunt tail bud unable to extend the body axis, failed to induce the synchronised expression of Notch1 and cyclic genes and cease the formation of new somites. Mechanistically, the interaction of PSM cells with the RGD motif of FN is required for dynamic formation of lamellipodia allowing motility and cell-cell contact formation, as these processes fail when wild type PSM cells are seeded into a FN matrix derived from FNRGE/RGE fibroblasts. Thus, α5β1-mediated adhesion to FN in the PSM regulates the dynamics of membrane protrusions and cell-to-cell communication essential for elongation and segmentation of the body axis.
Highlights
The vertebrate body axis elongates from anterior to posterior coinciding with the segmentation of the paraxial mesoderm into somites, which will form ribs, vertebral column and trunk muscles
These pathways induce the transcription of several cyclic genes, whose dynamic expression domains sweep from the posterior to the anterior presomitic mesoderm (PSM) with a periodicity that matches somite formation [1,2,3,4,5]
The motility gradient is possibly required to ensure a dynamic formation of cell-cell contacts between posterior PSM cells, which in turn sustains the coordinated expression of oscillating genes
Summary
The vertebrate body axis elongates from anterior to posterior coinciding with the segmentation of the paraxial mesoderm into somites, which will form ribs, vertebral column and trunk muscles. A molecular oscillator, which results from the coordinated signalling of Wnt, FGF and Notch pathways, orchestrates the rhythmic definition of the site where the PSM segments. These pathways induce the transcription of several cyclic genes, whose dynamic expression domains sweep from the posterior to the anterior PSM with a periodicity that matches somite formation [1,2,3,4,5]. The motility gradient is possibly required to ensure a dynamic formation of cell-cell contacts between posterior PSM cells, which in turn sustains the coordinated expression of oscillating genes
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