Rac1 Plays an Essential Role in Axon Growth and Guidance and in Neuronal Survival in the Central and Peripheral Nervous Systems

Overview

Journal Neural Dev

Publisher Biomed Central

Specialty Neurology

Date 2015 Sep 24

PMID 26395878

Citations 29

Authors

Zhong L Hua

Francesco E Emiliani

Jeremy Nathans

Affiliations

Soon will be listed here.

Abstract

Background: Rac1 is a critical regulator of cytoskeletal dynamics in multiple cell types. In the nervous system, it has been implicated in the control of cell proliferation, neuronal migration, and axon development.

Results: To systematically investigate the role of Rac1 in axon growth and guidance in the developing nervous system, we have examined the phenotypes associated with deleting Rac1 in the embryonic mouse forebrain, in cranial and spinal motor neurons, in cranial sensory and dorsal root ganglion neurons, and in the retina. We observe a widespread requirement for Rac1 in axon growth and guidance and a cell-autonomous defect in axon growth in Rac1 (-/-) motor neurons in culture. Neuronal death, presumably a secondary consequence of the axon growth and/or guidance defects, was observed in multiple locations. Following deletion of Rac1 in the forebrain, thalamocortical axons were misrouted inferiorly, with the majority projecting to the contralateral thalamus and a minority projecting ipsilaterally to the ventral cortex, a pattern of misrouting that is indistinguishable from the pattern previously observed in Frizzled3 (-/-) and Celsr3 (-/-) forebrains. In the limbs, motor-neuron-specific deletion of Rac1 produced a distinctive stalling of axons within the dorsal nerve of the hindlimb but a much milder loss of axons in the ventral hindlimb and forelimb nerves, a pattern that is virtually identical to the one previously observed in Frizzled3 (-/-) limbs.

Conclusions: The similarities in axon growth and guidance phenotypes caused by Rac1, Frizzled3, and Celsr3 loss-of-function mutations suggest a mechanistic connection between tissue polarity/planar cell polarity signaling and Rac1-dependent cytoskeletal regulation.

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References

Wang Y, Zhang J, Mori S, Nathans J . Axonal growth and guidance defects in Frizzled3 knock-out mice: a comparison of diffusion tensor magnetic resonance imaging, neurofilament staining, and genetically directed cell labeling. J Neurosci. 2006; 26(2):355-64. PMC: 6674392. DOI: 10.1523/JNEUROSCI.3221-05.2006. View

Erkman L, McEvilly R, Luo L, Ryan A, Hooshmand F, OConnell S . Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature. 1996; 381(6583):603-6. DOI: 10.1038/381603a0. View

Suo L, Lu H, Ying G, Capecchi M, Wu Q . Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase. J Mol Cell Biol. 2012; 4(6):362-76. DOI: 10.1093/jmcb/mjs034. View

Brault V, MOORE R, Kutsch S, Ishibashi M, Rowitch D, McMahon A . Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. Development. 2001; 128(8):1253-64. DOI: 10.1242/dev.128.8.1253. View

Sugihara K, Nakatsuji N, Nakamura K, Nakao K, Hashimoto R, Otani H . Rac1 is required for the formation of three germ layers during gastrulation. Oncogene. 1999; 17(26):3427-33. DOI: 10.1038/sj.onc.1202595. View

Yan J, Lu Q, Fang X, Adler P . Rho1 has multiple functions in Drosophila wing planar polarity. Dev Biol. 2009; 333(1):186-99. PMC: 2728161. DOI: 10.1016/j.ydbio.2009.06.027. View

Hall A, Lalli G . Rho and Ras GTPases in axon growth, guidance, and branching. Cold Spring Harb Perspect Biol. 2010; 2(2):a001818. PMC: 2828272. DOI: 10.1101/cshperspect.a001818. View

Masahira N, Takebayashi H, Ono K, Watanabe K, Ding L, Furusho M . Olig2-positive progenitors in the embryonic spinal cord give rise not only to motoneurons and oligodendrocytes, but also to a subset of astrocytes and ependymal cells. Dev Biol. 2006; 293(2):358-69. DOI: 10.1016/j.ydbio.2006.02.029. View

Tissir F, Bar I, Jossin Y, De Backer O, Goffinet A . Protocadherin Celsr3 is crucial in axonal tract development. Nat Neurosci. 2005; 8(4):451-7. DOI: 10.1038/nn1428. View

10.

Rattner A, Yu H, Williams J, Smallwood P, Nathans J . Endothelin-2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis. Proc Natl Acad Sci U S A. 2013; 110(40):E3830-9. PMC: 3791783. DOI: 10.1073/pnas.1315509110. View

11.

Wichterle H, Lieberam I, Porter J, Jessell T . Directed differentiation of embryonic stem cells into motor neurons. Cell. 2002; 110(3):385-97. DOI: 10.1016/s0092-8674(02)00835-8. View

12.

Hayashi K, Ohshima T, Mikoshiba K . Pak1 is involved in dendrite initiation as a downstream effector of Rac1 in cortical neurons. Mol Cell Neurosci. 2002; 20(4):579-94. DOI: 10.1006/mcne.2002.1144. View

13.

Ren T, Zhang J, Plachez C, Mori S, Richards L . Diffusion tensor magnetic resonance imaging and tract-tracing analysis of Probst bundle structure in Netrin1- and DCC-deficient mice. J Neurosci. 2007; 27(39):10345-9. PMC: 6673153. DOI: 10.1523/JNEUROSCI.2787-07.2007. View

14.

Chen L, Liao G, Waclaw R, Burns K, Linquist D, Campbell K . Rac1 controls the formation of midline commissures and the competency of tangential migration in ventral telencephalic neurons. J Neurosci. 2007; 27(14):3884-93. PMC: 6672412. DOI: 10.1523/JNEUROSCI.3509-06.2007. View

15.

Park A, Oh D, Lim S, Choi J, Moon J, Yu D . Regulation of dendritic arborization by BCR Rac1 GTPase-activating protein, a substrate of PTPRT. J Cell Sci. 2012; 125(Pt 19):4518-31. DOI: 10.1242/jcs.105502. View

16.

Tahirovic S, Hellal F, Neukirchen D, Hindges R, Garvalov B, Flynn K . Rac1 regulates neuronal polarization through the WAVE complex. J Neurosci. 2010; 30(20):6930-43. PMC: 6632643. DOI: 10.1523/JNEUROSCI.5395-09.2010. View

17.

Danielian P, Muccino D, Rowitch D, Michael S, McMahon A . Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol. 1998; 8(24):1323-6. DOI: 10.1016/s0960-9822(07)00562-3. View

18.

Chen J, Huang Y, Mazzoni E, Tan G, Zavadil J, Wichterle H . Mir-17-3p controls spinal neural progenitor patterning by regulating Olig2/Irx3 cross-repressive loop. Neuron. 2011; 69(4):721-35. PMC: 3062262. DOI: 10.1016/j.neuron.2011.01.014. View

19.

Marquardt T, Ashery-Padan R, Andrejewski N, Scardigli R, Guillemot F, Gruss P . Pax6 is required for the multipotent state of retinal progenitor cells. Cell. 2001; 105(1):43-55. DOI: 10.1016/s0092-8674(01)00295-1. View

20.

Habas R, Dawid I, He X . Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation. Genes Dev. 2003; 17(2):295-309. PMC: 195976. DOI: 10.1101/gad.1022203. View