Integration of PDGF and Adhesive Cell Signaling in Xenopus Mesendoderm Migration
Richardson, Crystal, Cell Biology - School of Medicine, University of Virginia
Desimone, Douglas, Department of Cell Biology, University of Virginia
Embryonic development requires precise regulation of large-scale tissue movements. During morphogenesis, many cell movements occur in response to chemokines, morphogens, and soluble growth factors that guide directional movement. Platelet-derived growth factor (PDGF) signaling is required for directional Xenopus mesendoderm migration on the fibrillar fibronectin (FN) matrix of the blastocoel roof. Gradients of PDGF ligand can direct cell migration ex vivo, but in the context of the developing embryo it remains unclear whether PDGF gradients are present. The PDGF ligand can attach to FN and act as a short-range signal. However, signaling via the PDGF receptor (PDGFr) can be upregulated without direct interaction with PDGF ligand but rather by cooperation with integrin receptors. Because the developing embryo is dynamic and gradients of soluble cues are difficult to regulate, the spatial-temporal regulation of PDGFr may be necessary for mesendoderm migration. The purpose of this dissertation is to evaluate the roles of integrin-dependent adhesive signaling and growth factor signaling during mesendoderm migration. I established a role for the PDGFr functioning independent of a PDGF ligand gradient in directional mesendoderm migration on FN. The PDGFr functions to modulate adhesion to FN by regulating the actin cytoskeleton and the size of focal adhesions in a manner that depends on signals from focal adhesion kinase (FAK) and Pi3k-Akt.
Integrin adhesion initiates the assembly of the extracellular matrix (ECM), and integrin activation requires talins and kindlins. During neurulation, several ECM proteins are assembled and remodeled at the somitic mesoderm and notochord boundary. This boundary forming ECM has essential roles in morphogenesis and is necessary for adhesion and orientation of tractive protrusions of mesoderm cells that undergo mediolateral intercalation behaviors during convergence and extension (CE). It has been demonstrated that perturbing FN results in severe defects in CE. I established a function for kindlin in the assembly of FN and fibrillin (FB) at the notochord somite boundary. This is the first demonstration of the role for kindlin functions in matrix assembly around the notochord. My dissertation describes how integrin-dependent adhesive signals can cooperate with growth factor signals for directional mesendoderm migration and how integrin activation by kindlin can regulate the assembly of the FN and FB matrix.
PHD (Doctor of Philosophy)
PDGF, integrin, migration, fibronectin