Control of axonal branching and synapse formation by focal adhesion kinase

Abstract

The formation of neuronal networks in the central nervous system (CNS) requires precise control of axonal branch development and stabilization. Here we show that cell-specific ablation of the murine gene Ptk2 (more commonly known as fak), encoding focal adhesion kinase (FAK), increases the number of axonal terminals and synapses formed by neurons in vivo. Consistent with this, fak mutant neurons also form greater numbers of axonal branches in culture because they have increased branch formation and reduced branch retraction. Expression of wild-type FAK, but not that of several FAK variants that prevent interactions with regulators of Rho family GTPases including the p190 Rho guanine nuclear exchange factor (p190RhoGEF), rescues the axonal arborization phenotype observed in fak mutant neurons. In addition, expression of a mutant p190RhoGEF that cannot associate with FAK results in a phenotype very similar to that of neurons lacking FAK. Thus, FAK functions as a negative regulator of axonal branching and synapse formation, and it seems to exert its actions, in part, through Rho family GTPases.

Focal adhesion kinase as a regulator of cell tension in the progression of cancer

“…Nevertheless, this correlation between FAK activity and adhesion growth, coupled with the observation that focal adhesion strength increases in response to an increase in force, suggests that FAK may be involved in a positive feedback loop involving focal adhesion growth, FAK activation, and the development of tension (Figure 3). In support of this model, mice in which FAK was specifically knocked out of Purkinje cells showed an abnormally high number of branched axons and synapses in the cerebellum, and this was attributed to an inability of neurons to retract due to a defect in the activation of the Rho pathway [62].…”

“…FAK -/-fibroblasts, and keratinocytes derived from mice with an epidermal-specific knockout of FAK, appear more contractile with large adhesions and an abundance of stress fibers [52,64]. However, FAK knockdowns in fibroblasts, epithelial, or endothelial cells, and fibroblasts or neurons derived from mice with a conditional knockout of FAK, exhibit an elongated or spindle-shaped morphology consistent with the inability of the cells to contract [65][66][67]62]. These new methods for inhibiting FAK expression along with recently-developed small molecules that inhibit FAK kinase activity [68,69], combined with methods to monitor the ability of the cells to contract [70,71], will shed new light on the role of FAK in regulating cell contraction and adhesion turnover.…”

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

“…FAK is a key intracellular regulator of migration in nonneuronal cells, acting by increasing turnover of focal adhesive contacts at the cell's leading edge. In neurons, FAK is more important as a negative regulator of dendritic and axonal branching than migration outgrowth [24,25]. This may be due to the existence of multiple pathways that converge on FAK in vivo.…”

Cellular mechanisms of estradiol-mediated masculinization of the brain

“…Using a high throughput western blot analysis we identified two related proteins, focal adhesion kinase (FAK) and paxillin, which are higher in the developing female hypothalamus and decreased by exogenous testosterone or estradiol (Speert and McCarthy unpublished observation). FAK has been implicated in neurite outgrowth [76], making it an attractive candidate for mediating hormonally-induced sex differences in neuronal branching and connectivity. However, causally connecting FAX and paxillin expression to female brain development remains a goal unmet.…”