Essential role of Rac1 and Rac3 GTPases in neuronal development

Abstract

Rac GTPases are members of the Rho family regulating the actin cytoskeleton and implicated in neuronal development. Ubiquitous Rac1 and neuron-specific Rac3 GTPases are coexpressed in the developing mammalian brain. We used Cre-mediated conditional deletion of Rac1 in neurons combined with knockout of neuron-specific Rac3 to study the role of these GTPases in neural development. We found that lack of both genes causes motor behavioral defects, epilepsy, and premature death of mice. Deletion of either GTPase does not produce evident phenotypes. Double-knockout mice show specific defects in the development of the hippocampus. Selective impairment of the dorsal hilus of double-knockout animals is associated with alteration in the formation of the hippocampal circuitry. Axonal pathways to and from the dorsal hilus are affected because of the deficit of hilar mossy cells. Moreover, analysis of Rac function in hippocampal cultures shows that spine formation is strongly hampered only in neurons lacking both Rac proteins. These findings show for the first time that both Rac1 and Rac3 are important for the development of the nervous system, wherein they play complementary roles during late stages of neuronal and brain development.

Src Homology 2 Domain Containing Protein 5 (SH2D5) Binds the Breakpoint Cluster Region Protein, BCR, and Regulates Levels of Rac1-GTP

“…Mice deficient for neuronal Rac1 and Rac3 die around postnatal day 13, due to impaired brain development from a reduction of axons and dendrites within the hippocampus. Furthermore, neurogenesis and synaptogenesis within the hippocampus are impaired and axonal projections are reduced in the hippocampus of these mutant mice (30).…”

Rho GTPases in embryonic development

“…58,63 The recent study by Vaghi et al (2012) investigating Rac1 and the neural specific Rac3 in the development of cortical and hippocampal GABAergic neurons suggests that both Rac1 and Rac3 contribute synergistically to the regulation of cortical and hippocampal neuronal migration and differentiation, which may explain the epileptic phenotype of the Rac1/Rac3 double mutant mice. 64,65 Lastly, several defects were also observed in the development of the cerebellum lacking Rac1. 66 Taken together, these studies clearly establish fundamental roles of RhoA, Rac1, and Cdc42 during early development of the CNS.…”

Rho GTPase isoforms in cell motility: Don't fret, we have FRET

“…99 In contrast, Rac3 and Rac1 appear to perform synergistic roles in the development of the nervous system as loss of both isoforms results in defects in the migration and differentiation of a number of brain cell types. [100][101][102][103] Loss of either isoform in the brain does not lead to obvious defects. 100 These results highlight that each of the Rac isoforms had been specialized for a very particular function and displays its own specific biology.…”

“…[100][101][102][103] Loss of either isoform in the brain does not lead to obvious defects. 100 These results highlight that each of the Rac isoforms had been specialized for a very particular function and displays its own specific biology.…”