| Budget Amount *help |
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 2004: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2003: ¥9,300,000 (Direct Cost: ¥9,300,000)
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| Research Abstract |
Evolution from unicellular protists to mulicellular animals is a crucial event in animal history. To address the molecular events occurred at this transition, we examined the functional alteration of Src tyrosine kinase, as a key molecular switch involved in the animal multicellularity. Orthologues of Src and its negative regulator Csk were molecular cloned from the unicellular choanoflagellate Monosiga ovata and the primitive multicellular sponge Ephydatia fluviatilis, and their activities and regulatory features were comparatively analyzed. Both organisms contain multiple forms of Src with all the domains involved in negative regulation and a functional Csk. In E.fluviatilis, multiple Src isoforms are stringently inhibited by Csk phosphorylation as in vertebrate. However, in M.ovata, Src retains robust activity even in the Csk phosphorylated form, due to deviations in the tertiary structure of the kinase domain. Inhibition of Src in choanoflagellates by the Src inhibitor promotes pol
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arized colony formation mediated by filopodia-like structures. These findings demonstrate that the appearance of Src and its regulatory components predates animal origins, but the regulatory system underwent a functional evolution accompanying the evolution of multicellularity.
To address the fundamental roles Src in the multicellular animals, Effects of loss-of-function of Src in C.elegans was analyzed. A mutation in the src-1 gene resulted in defective distal tip cell (DTC)-directed gonad morphogenesis in an activity dependent manner. The effect of the src-1 mutation was robustly suppressed by mutations in the genes located in a Rac pathway, which suggests that SRC-1 is an upstream regulator of the Rac pathway that controls cytoskeletal remodeling. The src-1 mutant also exhibits defects in neural cell migration. These findings suggest that SRC-1 plays an integral role in responding to the extracellular guidance cues that direct the cell migration occurring during development via a pathway that controls cytoskeletal remodeling. Less
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