TY - JOUR

T1 - Rac1 regulates neuronal polarization through the WAVE complex

AU - Tahirovic, Sabina

AU - Hellal, Farida

AU - Neukirchen, Dorothee

AU - Hindges, Robert

AU - Garvalov, Boyan K

AU - Flynn, Kevin C

AU - Stradal, Theresia E

AU - Chrostek-Grashoff, Anna

AU - Brakebusch, Cord

AU - Bradke, Frank

N1 - Keywords: Angiopoietins; Animals; Animals, Newborn; Apoptosis; Axons; Bromodeoxyuridine; Cell Movement; Cell Proliferation; Cells, Cultured; Cerebellum; Cofilin 1; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Growth Cones; Ki-67 Antigen; Luminescent Proteins; Mice; Mice, Knockout; Mutation; Nerve Tissue Proteins; Neurons; Organ Culture Techniques; RNA Interference; RNA, Small Interfering; Transfection; Wiskott-Aldrich Syndrome Protein Family; cdc42 GTP-Binding Protein; rac1 GTP-Binding Protein; rhoA GTP-Binding Protein

PY - 2010

Y1 - 2010

N2 - 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 verprolin-homologous 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.

AB - 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 verprolin-homologous 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.

U2 - 10.1523/JNEUROSCI.5395-09.2010

DO - 10.1523/JNEUROSCI.5395-09.2010

M3 - Journal article

C2 - 20484635

VL - 30

SP - 6930

EP - 6943

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

SN - 0270-6474

IS - 20

ER -