Neuronal Polarization and Axon Formation in Mice deficient in Rac1
Final Report Abstract
Neuronal polarization requires distinct changes in the cytoskeleton. While many key 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 knockout mouse, in which Rac1 is ablated in the whole brain. Rac1-deficient cerebellar granule neurons (CGNs), which do not express other Rac isoforms, showed impaired neuronal migration and axon formation both in vivo and in vitro. In addition, Rac1 ablation led to severe defects in lamellipodia formation in growth cones. The analysis of Rac1 effectors revealed the absence of the WAVE-complex from the plasma membrane of knockout growth cones. Loss of WAVE function inhibited axon growth while overexpression of a membrane-tethered WAVE mutant partially rescued axon growth in Rac1-knockout 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 remodelling necessary for neuronal differentiation and cerebellar development.
Publications
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(2008). Microtubule stabilization specifies initial neuronal polarization. J. Cell Biology 180:619-632
Witte H, Neukirchen D, Bradke F
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(2008). Plasticity of polarization: changing dendrites to axons in neurons integrated in neuronal circuits. Current Biology 18: 992-1000
Gomis-Rüth S, Wirenga CJ, Bradke F
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(2009). Chronically injured adult sensory axons in the CNS acquire axon regenerative competence following a lesion of their peripheral process. Current Biology 19:930-936
Ylera B, Ertürk A, Hellal F, Nadrigny F, Hurtado A, Tahirovic S, Oudega M, Kirchhoff F, Bradke F
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(2010). Axon extension occurs independently of centrosomal microtubule nucleation. Science 327:704-707
Stiess M, Maghelli M, Kapitein L, Gomis-Rüth S, Wilsch-Bräuninger M, Hoogenraad CC, Tolić-Nørrelykke IM, Bradke F
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(2010). Electrical activity suppresses axon growth through Cav1.2 channels in adult primary sensory neurons. Current Biology 20:1154-64
Enes J, Langwieser N, Ruschel J, Carballosa-Gonzalez MM, Klug A, Traut MH, Ylera B, Tahirovic S, Hofmann F, Stein V, Moosmang S, Hentall ID, Bradke F
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(2010). Rac1 regulates neuronal polarization through the WAVE-complex. J. Neurosci. 30: 6930-43
Tahirovic T, Hellal F, Garvalov BK, Chrostek-Grashoff A, Brakebusch C, Bradke F
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(2011). 3D imaging of the unsectioned adult spinal cord to assess axon regeneration and glial responses after injury. Nature Medicine 18:166-171
Ertürk A, Mauch CP, Hellal F, Förstner F, Keck T, Becker K, Jährling N, Steffens H, Richter M, Hübener M, Kramer E, Kirchhoff F, Dodt HU, Bradke F
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(2011). Cytoplasmic Linker Proteins Regulate Neuronal Polarization through Microtubule and Growth Cone Dynamics. J. Neuroscience 31:1528-38
Neukirchen D, Bradke F
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(2011). Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration After Spinal Cord Injury. Science 331:928-31
Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Umlauf M, Kapitein LC, Strikis D, Lemmon V, Bixby J, Hoogenraad CC, Bradke F
