Critical physiological and pathological processes, such as wound healing, de novo vessel angiogenesis and cancer metastasis, rely on directed collective cell migrations, whereby groups of cells become polarized and moves together in an orderly fashion. The ability of cell groups to migrate collectively is determined in part by the tissue-specific transcriptional inputs that define the complement of genes that they express and thus their competence to migrate. The long-term goal of this project is to understand how tissue-specific transcription regulators control the basic cellular processes underlying directed collective cell migration. To this aim, the simplified embryos of a chordate species, the ascidian Ciona intestinalis, will be used to study the migration of pre-cardiac mesoderm cells, called "trunk ventral cells" (TVCs). The TVCs provide the simplest possible model of directed collective cell migration in live embryos. On each side of the embryo, only two cells migrate together and display a clear Leader-Trailer (L-T) polarity aligned with the direction of migration: the leader TVC displays a broad leading edge and more conspicuous protrusions than the trailer. It was previously established that Mesp, Fibroblast Growth Factor (FGF) signaling and FoxF transcriptional inputs determine the ability of TVCs to migrate. The specific goal of the proposed research is to understand how transcriptional inputs contribute to the specification of the leader TVC and influence its protrusive activity. On the basis of preliminary observations, the hypotheses that (1) a ventral source of bone morphogenetic proteins (BMP) contributes to the L-T polarized expression of downstream target genes, including the Lef/Tcf transcription factor;and (2) these transcriptional inputs determine the L-T polarized activities of the Rho GTPases RhoDF and Cdc42, which are required for the formation of membrane protrusions will be tested. To address these possibilities, the expression, cis-regulation and function of Lef/Tcf in the TVCs will first be analyzed in order to understand L-T polarized transcriptional inputs. Second, quantitative imaging methods will be used to document the L-T polarization of RhoDF, Cdc42 and protrusive activities in wild-type conditions and after manipulations of transcription regulators and other candidate Rho GTPases in an attempt to characterize their effects on L-T polarized membrane protrusions. Finally, candidate regulated effectors of collective cell polarization and protrusive activity will be identified using TVC-specific whole genome microarray analysis followed by systematic expression and functional analyses by in situ hybridization and targeted over-expression, respectively. The expectation is to determine a mechanism of transcriptional control for collective cell migration by characterizing the transcription regulators, the regulated effectors and their effects on the Rho GTPase signaling and actin filament dynamics that underlie collective cell polarization and the formation of membrane protrusions.
In animals, including humans, a variety of morphogenetic processes known as collective cell migrations are essential for physiological and pathological phenomena such as embryonic development, wound healing, de novo vessel formation and cancer metastasis. We propose to study the molecular and cellular mechanisms that control directed collective cell migration using the simplest possible model, which consists of two cells migrating as a polarized pair in embryos of the marine invertebrate, the tunicate Ciona intestinalis. Because of the evolutionary proximity with vertebrates, studies using this simple model will decipher the basic mechanisms driving collective cell migration with potential applications for regenerative medicine and the prevention of cancer metastasis.
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