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Reelin signals through Apoer2 and Cdc42 to increase growth cone motility and filopodia formation

A. Growth cone motility and neurite branch formation are activated (+) by Rac1 and Cdc42 and negatively regulated (-) by RhoA. Reelin participates in the regulation of growth cone motility and branching by regulating Rho GTPase activity (B). Filopodia formation and the formation of neuronal transport vesicles, both known to be mediated by Cdc42, are triggered by Reelin.

B. Binding of the extracellular matrix protein Reelin to its transmembrane receptors Apoer2 and Vldlr triggers Dab1 tyrosine phosphorylation by Src-family-kinases (SFK). This leads to the activation of several downstream signals, including phosphatidylinositol-3-kinase (PI3K), which activates Cdc42 via an unknown intermediate effector. There is evidence that Reelin also might locally activate Rac1. N-WASP and WAVE link Cdc42 and Rac1 activity to changes of the actin cytoskeleton, leading to increased growth cone motility, filopodia and vesicle formation, and dendritic branching (A). Cdc42 and Rac1 also contribute to activation of the PAK/LIMK pathway, which inhibits actin filament disassembly by phosphorylating the actin-depolymerizing factor ADF/cofilin leading to growth inhibition or stabilization of filopodia. The fine tuning of these context-dependent convergent or divergent pathways downstream of Rho GTPases is fundamental for correct neuronal development.

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