title: Rac1 plays an essential role in axon growth and guidance and in neuronal survival in the central and peripheral nervous systems.
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.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. zhuajhu@gmail.com.|Present address: Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA. zhuajhu@gmail.com.
authors.forename: Zhong L
authors.initials: ZL
authors.lastname: Hua
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. femilia1@jhu.edu.
authors.forename: Francesco E
authors.initials: FE
authors.lastname: Emiliani
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jnathans@jhmi.edu.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jnathans@jhmi.edu.|Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jnathans@jhmi.edu.|Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jnathans@jhmi.edu.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D019521:Body Patterning; D002470:Cell Survival; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000196:embryology / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000502:physiology*; D013116:Spinal Cord / Q000196:embryology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein