Cdc42 Regulates Cofilin during the Establishment of Neuronal Polarity

Abstract

The establishment of polarity is an essential process in early neuronal development. Although a number of molecules controlling neuronal polarity have been identified, genetic evidence about their physiological roles in this process is mostly lacking. We analyzed the consequences of loss of Cdc42, a central regulator of polarity in multiple systems, on the polarization of mammalian neurons. Genetic ablation of Cdc42 in the brain led to multiple abnormalities, including striking defects in the formation of axonal tracts. Neurons from the Cdc42 null animals sprouted neurites but had a strongly suppressed ability to form axons both in vivo and in culture. This was accompanied by disrupted cytoskeletal organization, enlargement of the growth cones, and inhibition of filopodial dynamics. Axon formation in the knock-out neurons was rescued by manipulation of the actin cytoskeleton, indicating that the effects of Cdc42 ablation are exerted through modulation of actin dynamics. In addition, the knock-outs showed a specific increase in the phosphorylation (inactivation) of the Cdc42 effector cofilin. Furthermore, the active, nonphosphorylated form of cofilin was enriched in the axonal growth cones of wild-type, but not of mutant, neurons. Importantly, cofilin knockdown resulted in polarity defects quantitatively analogous to the ones seen after Cdc42 ablation. We conclude that Cdc42 is a key regulator of axon specification, and that cofilin is a physiological downstream effector of Cdc42 in this process.

Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics

“…In WT neurons, cofilin S3A enhanced neurite growth (Fig. 6T), as reported previously (41). In SRF-deficient neurons, cofilin S3A expression resulted in neurite outgrowth comparable to that of WT neurons (Fig.…”

The Rho GTPase Cdc42 is required for primary mammary epithelial cell morphogenesis in vitro

“…Knockout of Cdc42 in embryonic stem cells grown in suspension as embryoid bodies demonstrated that Cdc42 is required for establishment of apical polarity and formation of adherens and tight junctions during embryogenesis. 34 Similarly, Cdc42 knockout keratinocytes showed defects in maturation of adherens junctions. 35 In both embryoid bodies and keratinocytes, these defects correlated with aberrant activation and localization of PKCζ.…”

Small molecule targeting Cdc42–intersectin interaction disrupts Golgi organization and suppresses cell motility

“…Cdc42 has been attributed to several aspects of cancer, including cellular transformation (10) and metastasis (11,12). As a key regulator of neurite morphogenesis, Cdc42 has also been shown to be crucial for normal brain development, as conditional Cdc42 KO mice do not survive birth and show gross brain abnormalities (8,13).…”