Cell adhesion molecules (CAMs) appear at specific times and places during development and govern border formation and tissue patterning. This prompts the hypothesis that the place-dependent expression, binding, and signaling functions of CAMs are all critical for the regulation of morphogenesis. In accord with this hypothesis, recent results indicated that the place-dependent expression of CAMs during development is regulated by homebox (Hox) and paired box (PAX) genes and that cell-cell binding medicated by CAMs in turn sends signals to the nucleus to affect gene expression including the expression of CAM genes themselves. The goal of the investigators' studies is to analyze the changes in cellular signaling and gene expression that occur after cell-cell binding mediated by N-CAM.
In aim I, the proposed studies will examine the interaction of N-CAM extracellular domains during homphilic binding and determine the intracellular interactions of N-CAM cytoplasmic domains.
In aim II, signal pathways and changes in gene expression in astrocytes activated by N-CAM binding will be examined and compared to what is known about such pathways and changes in neurons. This approach is based on the finding that binding of N-CAM and its domains to astrocytes strongly inhibits their proliferation and induces differential gene expression.
In aim III, the effects of the presence or absence of N-CAM on gene expression will be studied in vivo by using specific gene probes and subtractive hybridization in knockout mice lacking all forms of N-CAM. Studies will be carried out to determine whether the absence of N-CAM during development affects the expression patterns in particular tissues of a variety of genes, including Hox genes, Pax genes, and CAM genes themselves.
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