Abstract
BackgroundRac1 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.ResultsTo 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.ConclusionsThe 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.
Highlights
IntroductionIt has been implicated in the control of cell proliferation, neuronal migration, and axon development
Rac1 is a critical regulator of cytoskeletal dynamics in multiple cell types
To compare axon growth and guidance phenotypes produced by loss of Rac1 with our earlier studies of Fz3 lossof-function mutations in the forebrain, we immunostained coronal sections of E18.5 Foxg1-Cre;Rac1CKO/− and control Rac1CKO/+ brains for neurofilament and compared them to an analogous set of coronal sections from Foxg1Cre;Fz3CKO/− embryos, shown in Figures 1 and 2 of Hua et al [18]. (Foxg1-Cre is expressed prior to E10.5 in the anterior neural tube, leading to Cre-mediated recombination in all or most CNS cell types in the developing telencephalon)
Summary
It has been implicated in the control of cell proliferation, neuronal migration, and axon development. A widely expressed member of the Rho GTPase family, controls actin dynamics and plays an essential role in cell proliferation and migration in multiple contexts [2]. Rac in the anterior neural tube starting at embryonic day (E)8.5 permits survival until birth, and at late gestation, these embryos show an absence of the anterior commissure, a failure of the corpus callosum and hippocampal commissure to cross the midline, and defects in corticothalamic and thalamocortical projections [4]. Selective deletion of Rac in the cerebral cortex blocks midline crossing of axons in the corpus callosum and anterior commissure, but there is little or no effect on the development of the corticospinal, corticothalamic, and thalamocortical tracts [7]
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