Rac1 in cortical projection neurons is selectively required for midline crossing of commissural axonal formation

Abstract

Rac1 is a member of Rho family GTPases and regulates multiple cellular functions through actin cytoskeleton reorganization. During cerebral corticogenesis, Rac1 has been assumed to be involved in neuronal migration, neurite formation, polarization and axonal guidance. Here we show the specific role of Rac1, regulating midline crossing of commissural axons during cortical development by using cortex-restricted Rac1-knockout mice. In the knockout mice, Rac1 was eliminated from the beginning of corticogenesis exclusively in the dorsal telencephalon where progenitors of cortical projection neurons are located. Cortical lamination was distorted only mildly in the knockout mice, being preserved with six layers of neurons. However, cortex-restricted Rac1 deletion exhibited striking agenesis of commissural axons including the corpus callosum and anterior commissure without affecting other corticofugal axons including corticospinal and corticothalamic projections. Of note, the commissural axons of the knockout mice were potent in extending their process, but failed to cross the midline. Therefore, these findings indicate that Rac1 specifically controls the midline crossing of the commissural fibers, but not axonal formation of corticospinal or corticothalamic fibers during cortical development.

Rac1 Regulates Neuronal Polarization through the WAVE Complex

“…restricted Rac1-knock-out mice is not impaired (Kassai et al, 2008). Here, we showed that Rac1 signaling is essential for efficient migration of one of the largest population of neurons in the brain, CGNs.…”

“…Rac1 and Rac3 are present in the nervous system (Didsbury et al, 1989;Bolis et al, 2003), and the expression of mutant Racs causes aberrant axon formation in mouse and chick neurons (Luo et al, 1996;Albertinazzi et al, 1998). By contrast, deletion of Rac3 or specific ablation of Rac1 in the mouse cortex does not affect axon growth (Corbetta et al, 2005;Chen et al, 2007;Gualdoni et al, 2007;Kassai et al, 2008). This suggests that axon growth may be independent of Rac activity.…”

“…However, axon growth defects could not be observed (Chen et al, 2007;Kassai et al, 2008). One potential reason for the normal polarization of the Rac1-ablated cortical neurons is that Rac3 may compensate for some Rac1-dependent functions (Bolis et al, 2003;Corbetta et al, 2009).…”

“…However, this idea has been challenged in recent in vivo studies, showing that Rac1 is dispensable for the migration of many neuronal and non-neuronal cells, including fibroblasts, macrophages, leukocytes, and cortical neurons (Bokoch, 2005;Vidali et al, 2006;Wheeler et al, 2006;Kassai et al, 2008).…”

Rho GTPases in embryonic development

“…Since Rac1 is an important signaling mediator of many classic axon guidance cues, including the netrin/DCC signaling pathway, [57][58][59][60] it was not so surprising to observe a complete absence of the anterior commissure in the brain of Rac1-deficient embryos. 55,61 Furthermore, the corpus callosal and the hippocampal commissural axons failed to cross the midline in Rac1-deficient embryos while there was also projection and defasciculation defects of the corticothalamic and thalamocortical axons. However, no defect in the axonal outgrowth of telencephalic neurons was observed in Rac1-deficient embryos but a reduction in cortical interneurons within the cortex indicated a defect in tangential migration.…”