Rac1 Regulates Neuronal Polarization through the WAVE Complex

Abstract

Neuronal migration and axon growth, key events during neuronal development, require distinct changes in the cytoskeleton. Although many molecular regulators of polarity have been identified and characterized, relatively little is known about their physiological role in this process. To study the physiological function of Rac1 in neuronal development, we have generated a conditional knock-out mouse, in which Rac1 is ablated in the whole brain. Rac1-deficient cerebellar granule neurons, which do not express other Rac isoforms, showed impaired neuronal migration and axon formation both in vivo and in vitro. In addition, Rac1 ablation disrupts lamellipodia formation in growth cones. The analysis of Rac1 effectors revealed the absence of the Wiskott-Aldrich syndrome protein (WASP) family verprolinhomologous protein (WAVE) complex from the plasma membrane of knock-out growth cones. Loss of WAVE function inhibited axon growth, whereas overexpression of a membrane-tethered WAVE mutant partially rescued axon growth in Rac1-knock-out neurons. In addition, pharmacological inhibition of the WAVE complex effector Arp2/3 also reduced axon growth. We propose that Rac1 recruits the WAVE complex to the plasma membrane to enable actin remodeling necessary for axon growth.

Cytoplasmic Linker Proteins Regulate Neuronal Polarization through Microtubule and Growth Cone Dynamics

“…Consistent with this possibility, specific microtubule-dependent motor proteins, including kinesin-1, transport vesicles preferentially on stable microtubules and become enriched before morphological polarization (Jacobson et al, 2006;Reed et al, 2006;Konishi and Setou, 2009). If the transported cargo contains limiting factors for axon growth, for example microtubule stabilizers including CLIPs or actin regulators such as the Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein (WAVE) (Kawano et al, 2005;Yokota et al, 2007;Tahirovic et al, 2010), the axon would enrich in those factors while the minor neurites would become depleted of them. Hence, CLIP-mediated stabilization of microtubules might be one entry site to induce a re-enhancing loop to form an axon.…”

Regulation of cell adhesion and migration in cortical neurons

“…Consistent with this, BrdU-pulse labeling experiments using Rac1-conditional knockout mice show that neuronal migration is delayed in both the cerebrum and cerebellum, although the migration-defect in the cerebral cortices of the conditional knockout mice is milder than that observed in the dominant negative experiments probably due to compensation by Rac3 or other Rho family small GTPases. 11,12 Furthermore, in vivo suppression of STEF/Tiam1, guanine nucleotide exchange factors (GEFs) for Rac1, strongly inhibits neuronal migration, whereas functional suppression of P-Rex1, another Rac1 GEF, exhibits much milder neuronal migration defects, suggesting that several GEFs differentially regulate Rac1 activity to promote neuronal migration. 10,13 The fact that DN-Rac1 disturbs multipolar cell morphology implicates that one of the downstream pathways of Rac1 (pial surface) side in G 1 .…”

“…12 Furthermore, Rac1 is reported to function in neural progenitors prior to neural differentiation and migration. Rac1 deficiency causes the reduction of neural progenitors due to enhanced cell cycle exit and decreased cell survival.…”

Rho GTPases in embryonic development

“…64,65 Lastly, several defects were also observed in the development of the cerebellum lacking Rac1. 66 Taken together, these studies clearly establish fundamental roles of RhoA, Rac1, and Cdc42 during early development of the CNS.…”