Cortactin binding protein 2 increases microtubule stability and regulates dendritic arborization

Abstract

Neurons are characterized by subcellular compartments, such as axons, dendrites and synapses, that have highly specialized morphologies and biochemical specificities. Cortactin-binding protein 2 (CTTNBP2), a neuron-specific F-actin regulator, has been shown to play a role in the regulation of dendritic spine formation and their maintenance. Here, we show that, in addition to F-actin, CTTNBP2 also associates with microtubules before mature dendritic spines form. This association of CTTNBP2 and microtubules induced the formation of microtubule bundles. Although the middle (Mid) region of CTTNBP2 was sufficient for its association with microtubules, for microtubule bundling, the Nterminal region containing the coiled-coil motifs (NCC), which mediates the dimerization or oligomerization of CTTNBP2, was also required. Our study indicates that CTTNBP2 proteins form a dimer or oligomer and brings multiple microtubule filaments together to form bundles. In cultured hippocampal neurons, knockdown of CTTNBP2 or expression of the Mid or NCC domain alone reduced the acetylation levels of microtubules and impaired dendritic arborization. This study suggests that CTTNBP2 influences both the F-actin and microtubule cytoskeletons and regulates dendritic spine formation and dendritic arborization.

A de novo interstitial deletion of 7q31.2q31.31 identified in a girl with developmental delay and hearing loss

“…It is thus proposed that CTTNBP2 has an essential role in dendritic spine formation and maintenance [Chen and Hsueh, ; Chen et al, ]. In addition to F‐actin, CTTNBP2 also associates with microtubules to promote microtubule bundle formation and dendritic arborization [Shih et al, ]. ANKRD7 is specifically expressed in Sertoli cells in the testis and may be involved in spermatogenesis [Shi et al, ].…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Cortactin acts downstream of CTTNBP2 in spine morphogenesis, as the defects caused by CTTNBP2 knockdown can be rescued by cortactin overexpression but not by overexpressing a CTTNBP2 mutant protein that cannot bind cortactin 37 . Furthermore, CTTNBP2 oligomerization has been shown to promote dendritic arborization through microtubule bundling 40 . Several mutations of CTTNBP2 gene have been reported in ASD cases [41][42][43] , indicating the importance of correct dendritic spine structure and density for proper brain function.…”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…CTTNBP2 is highly expressed in dendritic spines where it locally interacts with cortactin, striatin, a calcium binding protein, and PP2A, a serine/threonine protein phosphatase 2A, to control the formation and the maintenance of dendritic spines (Chen et al, 2012; Chen and Hsueh, 2012; Hsueh, 2012). In addition, oligomerization of CTTNBP2 induces microtubule bundling to promote dendrite arborization (Shih et al, 2014). Several mutations of CTTNBP2 have been reported in ASD cases, further indicating the importance of neurite outgrowth and dendritic spine formation for proper brain function (Cheung et al, 2001; Iossifov et al, 2012; De Rubeis et al, 2014).…”