Cortactin-Binding Protein 2 Modulates the Mobility of Cortactin and Regulates Dendritic Spine Formation and Maintenance

Abstract

Dendritic spines, the actin-rich protrusions emerging from dendrites, are the locations of excitatory synapses in mammalian brains. Many molecules that regulate actin dynamics also influence the morphology and/or density of dendritic spines. Since dendritic spines are neuron-specific subcellular structures, neuron-specific proteins or signals are expected to control spinogenesis. In this report, we characterize the distribution and function of neuron-predominant cortactin-binding protein 2 (CTTNBP2) in rodents. An analysis of an Expressed Sequence Tag database revealed three splice variants of mouse CTTNBP2: short, long, and intron. Immunoblotting indicated that the short form is the dominant CTTNBP2 variant in the brain. CTTNBP2 proteins were highly concentrated at dendritic spines in cultured rat hippocampal neurons as well as in the mouse brain. Knockdown of CTTNBP2 in neurons reduced the density and size of dendritic spines. Consistent with these morphological changes, the frequencies of miniature EPSCs in CTTNBP2 knockdown neurons were lower than those in control neurons. Cortactin acts downstream of CTTNBP2 in spinogenesis, as the defects caused by CTTNBP2 knockdown were rescued by overexpression of cortactin but not expression of a CTTNBP2 mutant protein lacking the cortactin interaction. Finally, immunofluorescence staining demonstrated that, unlike cortactin, CTTNBP2 stably resided at dendritic spines even after glutamate stimulation. Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines.

Leucine-Rich α2-Glycoprotein Is a Novel Biomarker of Neurodegenerative Disease in Human Cerebrospinal Fluid and Causes Neurodegeneration in Mouse Cerebral Cortex

“…In addition, LRG demonstrates a strong affinity with cortactin, which exists in neuronal dendrites [46,47]. We speculated that strong binding of LRG with these proteins impedes synaptic function, reduces cognitive function, and is related to neuronal loss.…”

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

“…(Cttn), which was also found to be downregulated in KA-injected mice at 1dpi (0.53 fold), 3dpi (0.47 fold) and at 30dpi (0.13 fold) 58 . Neuron specific microtubuleassociated proteins Map1a, Map2, tau (Mapt), Map1b and Map6, participating in the development of neuronal polarity [59][60][61][62][63][64] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 30dpi (0.59 fold).…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…has been shown to regulate the mobility and distribution of cortactin which, in turn, controls dendritic spine morphogenesis via F-actin branching and stabilization [36][37][38] ( Figure 1). Cortactin expression supression 39 and CTTNBP2 knockdown in neurons 37 reduce the spine density 39 , indicating their importance for the formation and maintenance of the spines.…”

“…Cortactin expression supression 39 and CTTNBP2 knockdown in neurons 37 reduce the spine density 39 , indicating their importance for the formation and maintenance of the spines. 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 .…”