Article

Focal Adhesion Kinase Acts Downstream of EphB Receptors to Maintain Mature Dendritic Spines by Regulating Cofilin Activity

Division of Biomedical Sciences and Neuroscience Program, University of California, Riverside, Riverside, California 92521-0121, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 07/2009; 29(25):8129-42. DOI: 10.1523/JNEUROSCI.4681-08.2009
Source: PubMed

ABSTRACT Dendritic spines are the postsynaptic sites of most excitatory synapses in the brain and are highly enriched in polymerized F-actin, which drives the formation and maintenance of mature dendritic spines and synapses. We propose that suppressing the activity of the actin-severing protein cofilin plays an important role in the stabilization of mature dendritic spines, and is accomplished through an EphB receptor-focal adhesion kinase (FAK) pathway. Our studies revealed that Cre-mediated knock-out of loxP-flanked fak prompted the reversion of mature dendritic spines to an immature filopodial-like phenotype in primary hippocampal cultures. The effects of FAK depletion on dendritic spine number, length, and morphology were rescued by the overexpression of the constitutively active FAK(Y397E), but not FAK(Y397F), indicating the significance of FAK activation by phosphorylation on tyrosine 397. Our studies demonstrate that FAK acts downstream of EphB receptors in hippocampal neurons and EphB2-FAK signaling controls the stability of mature dendritic spines by promoting cofilin phosphorylation, thereby inhibiting cofilin activity. While constitutively active nonphosphorylatable cofilin(S3A) induced an immature spine profile, phosphomimetic cofilin(S3D) restored mature spine morphology in neurons with disrupted EphB activity or lacking FAK. Further, we found that EphB-mediated regulation of cofilin activity at least partially depends on the activation of Rho-associated kinase (ROCK) and LIMK-1. These findings indicate that EphB2-mediated dendritic spine stabilization relies, in part, on the ability of FAK to activate the RhoA-ROCK-LIMK-1 pathway, which functions to suppress cofilin activity and inhibit cofilin-mediated dendritic spine remodeling.

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    • "It is becoming more evident that dynamic modulation of proteins involved in actin regulation is required for spine development and plasticity (Hotulainen and Hoogenraad, 2010; Pertz, 2010). For example, knockdown of cofilin-1 by siRNA and overexpression of constitutively active cofilin-1 induces similar phenotype in developing neurons: long filopodia-like structures (Hotulainen et al., 2009; Shi et al., 2009). Similarly, both long-term increase and decrease of Rac1 activity leads to reduced number of normal spines and synapses (Nakayama et al., 2000; Zhang et al., 2003). "
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    • "A distinct Ig-class adhesion molecule, SynCAM1, has been shown to have an opposing effect in stimulating spine growth and excitatory synapse formation in the hippocampus (Robbins et al., 2010). NrCAM might be a bidirectional regulator of spine development and/or plasticity as it physically associates with EphB2, a tyrosine kinase receptor that stabilizes dendritic spines (Shi et al., 2009) and modulates ankyrin B binding to NrCAM by phosphorylating a critical tyrosine residue in the NrCAM cytoplasmic domain (Dai et al., 2013). The cortical expression pattern and localization of NrCAM on dendritic spines of star pyramidal cells, coupled with the ability of NrCAM to rescue Sema3F-induced spine collapse when reexpressed in NrCAM-minus cortical neurons support a postsynaptic role for NrCAM in spine remodeling/elimination. "
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    • "ic spine remod - eling during spine growth ( Hotulainen et al . , 2009 ) . As mentioned above , cofilin is another critical determinant of actin skeletal dynamics and competes with the Arp2 / 3 complex by severing and debranching actin filaments ( Chan et al . , 2009 ) . Although prolonged cofilin activa - tion promotes a reduction in spine size ( Shi et al . , 2009 ) , it appears that a transient burst of cofilin activity is required for spine growth during chemically induced LTP ( Gu et al . , 2010 ) . A recent review of small GTPase control of the actin cytoskeleton covers these pathways in greater detail ( Penzes and Cahill , 2012 ) . Overall , a stereotyped spine - morphogenic signaling cascad"
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