Sci. STKE, 21 January 2003
Neuronal Development Neurons Making Par
Shi et al. investigated the role of Par3 and Par 6, two proteins implicated in Caenorhabditis elegans and Drosophila polarization, and determined that they were crucially involved in neuronal polarization as well. Most developing neurons produce one long axon and multiple dendrites, a process that involves differences in cytoskeletal dynamics of the developing neurites. The molecular mechanisms by which the developing neurites become polarized, however, are unclear. Shi et al. used immunofluorescent analysis of primary cultures of rat hippocampal neurons to demonstrate that mPar3, which acts as a scaffold for a protein complex containing mPar6, atypical protein kinase C (aPKC), and the activated forms of the actin cytoskeleton regulators Cdc42 and Rac1, was found throughout neurites early in development. However, mPar3 was localized to the newly developing axon as neurons became polarized. Neurons transfected with mPar3, or mPar3 mutants containing the NH2-terminal, expressed mPar3 ectopically and did not become polarized. Endogenous mPar6 showed similar polarized distribution and ectopically expressed mPar6 also inhibited polarization. The authors used selective inhibitors to show that aPKC activity was also required for polarization. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K), which was concentrated at the axon tip, or of growth factor tyrosine kinase, as well as overexpression of a phosphatase that degrades phosphatidylinositol-3,4,5-trisphosphate, all inhibited neuronal polarization. PI3K activity was also required for mPar3 localization to neurites. These data implicate the mPar3, mPar6, aPKC multiprotein complex in neuronal polarization and suggest that this complex acts downstream of a PI3K pathway.
S.-H. Shi, L. Y. Jan, Y.-H. Jan, Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112, 63-75 (2003). [Online Journal]
G. Banker, Pars, PI 3-kinase, and the establishment of neuronal polarity. Cell 112, 4-5 (2003). [Online Journal]
Citation: Neurons Making Par. Sci. STKE 2003, tw34 (2003).
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