Collective cell migration is necessary for morphogenesis and diseases progression. Cells undergo collective cell migration during wound healing, regeneration, embryonic development, and cancer metastasis. [1, 2] Most cell migration studies have been done on single cells in culture. [3, 4] However, in vivo many cells migrate as groups maintaining contacts with neighboring cells. Often these contacts are required for directional migration. [5] For example, several cell types migrate randomly as single cells, but migrate directionally when cell-cell contacts are formed. [6, 7] As cells migrate collectively they exert mechanical forces on one another and on surrounding tissues. [8] My goal is to understand how cell-cell contacts influence cell polarity to result in directed collective cell migration. Few systems are amenable to studies of collective cell migration, leaving the molecular mechanisms that coordinate collective cell behaviors unclear. The goal of this research plan is to elucidate mechanisms of collective cell migration using the mesendoderm of gastrulating Xenopus laevis embryos as a model system. Mesendoderm migration is a particularly good model of collective cell migration behaviors because in vivo tissue movements are recapitulated with good fidelity in cultured explants of mesendodermal tissue. [6, 7, 12, 13] A recent finding in our lab demonstrates that application of mechanical force to cell-cell adhesions is sufficient to recruit a network of keratin intermediate filaments to cadherin adhesions and orient protrusions to direct migration. [6] The proposal seeks to further understand this biomechanical mechanism by investigating the role of Wnt-Fz/PCP and PDGF signaling in this process. Wnt- Frizzled (Fz) /Planar Cell Polarity (PCP) and Platelet Derived Growth Factor (PDGF) are both signal transduction pathways that regulate cell protrusive polarity in mesendoderm [9, 10, 11], but the role of these pathways in coordinating collective behaviors is not well understood.
Aim 1 will elucidate the role of Wnt- Fz/PCP and PDGF signaling in influencing mechanosensitive directional protrusion formation.
Aim 2 will further the understanding of whether Wnt-Fz/PCP and/or PDGF signaling is required for organization of cytoskeletal filaments required for collective cell migration.
Aim 3 will test whether mechanical Wnt-Fz/PCP and PDGF signaling contribute to spatiotemporal mechanical force distribution during collective cell migration. Together these aims will identify mechanisms for how Wnt-Fz/PCP and PDGF signaling regulate mesendoderm migration. Overall this study will increase our understanding of how cell behaviors are coordinated to produce collective movements.
Morphogenesis, wound healing and the progression of many disease states require careful coordination of cell behaviors. [1] Many cell types migrate as tissues exerting mechanical forces on one another and the surrounding microenvironment, yet the molecular mechanisms underlying large-scale tissue movements remain unclear. [8] This research plan will uncover how soluble guidance cues and mechanical forces combine to influence tissue migration.
