Cell migration plays a central role in embryonic development, wound healing, inflammation and tumor metastasis. A key step is to elucidate the molecular interactions between cells and the substrata on which cells migrate. This proposal focuses on the role of a cell adhesion receptor, alpha4beta1, in cell migration during mouse development. We have generated a mouse model in which the lacZ reporter gene is knocked-in at the alpha4 integrin locus, replacing alpha4 with lacZ and placing lacZ under the control of the alpha4 promoter. Analysis of this mouse has revealed an essential role of alpha4beta1 in the migration of epicardial progenitor cells during cardiac development. In the first aim, we will extend our analysis on this mouse model and identify new roles for alpha4beta1 in other migratory events during development. We will also study the in vivo functions of alpha4beta1 in later stages of development by knocking-out alpha4 conditionally or in specific tissues. It has been shown by others that in cultured cells alpha4beta1 promotes cell migration in a unique way. However, little is known as to how alpha4beta1 regulates cell migration in vivo. It has been hypothesized that integrins may regulate cell migration through inside-out and outside-in signaling events.
In Aim 2, we will use a mouse knock-in strategy to test subtle mutations in alpha4 that disrupt inside-out or outside-in signaling. We will determine if alpha4 cDNAs carrying these mutations can rescue the epicardial migration defect caused by the alpha4-null mutation. These studies will allow us to elucidate mechanisms by which alpha4beta1-dependent migration is regulated.
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