Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation

Abstract

Genetic variations in dysbindin-1 (dystrobrevin-binding protein-1) are one of the most commonly reported variations associated with schizophrenia. As schizophrenia could be regarded as a neurodevelopmental disorder resulting from abnormalities of synaptic connectivity, we attempted to clarify the function of dysbindin-1 in neuronal development. We examined the developmental change of dysbindin-1 in rat brain by western blotting and found that a 50 kDa isoform is highly expressed during the embryonic stage, whereas a 40 kDa one is detected at postnatal day 11 and increased thereafter. Immunofluorescent analyses revealed that dysbindin-1 is enriched at the spine-like structure of primary cultured rat hippocampal neurons. We identified WAVE2, but not N-WASP, as a binding partner for dysbindin-1. We also found that Abi-1, a binding molecule for WAVE2 involved in spine morphogenesis, interacts with dysbindin-1. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. RNA interference-mediated knockdown of dysbindin-1 led to the generation of abnormally elongated immature dendritic protrusions. The present results indicate possible functions of dysbindin-1 at the postsynapse in the regulation of dendritic spine morphogenesis through the interaction with WAVE2 and Abi-1.

Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila

“…Second, although a developmental role of dysbindin has been reported earlier (23,24) and is supported, as mentioned above (Fig. S6 and Table S1), both neurotransmitter and behavioral phenotypes examined in this study could be rescued through acute treatments (Figs.…”

Expression and Y435-phosphorylation of Abelson interactor 1 (Abi1) promotes tumour cell adhesion, extracellular matrix degradation and invasion by colorectal carcinoma cells

“…In a previous study, we could show that heterogeneous nuclear ribonucleoprotein K, a 65kD protein that has the ability to act as a translational regulator via binding to mRNA transcripts, interacts with Abi1 in hippocampal neurons and exerts a similar effect on synaptic maturation [9]. The role of Abi1 in cytoskeletal dynamics during lamellipodia formation has been linked to its ability to join the WAVE multiprotein complex including Abi1, Nap1, HSPC300 and Sra/PIR121 [10,11]; the active complex brings bound Arp2/3 and actin monomers into close proximity, thus enhancing actin polymerization [12]. Accordingly, Abi1-deficient mouse embryos show malformations in the developing heart and brain and die around embryonic day 11; furthermore, they show decreased integrity and function of the WAVE complex [13].…”

Biochemical and Morphological Characterization of a Neurodevelopmental Disorder-Related Mono-ADP-Ribosylhydrolase, MACRO Domain Containing 2

“…Mouse MacroD2, MacroD1, and OARD1 cDNAs were obtained by RT-PCR with total RNA pool from E16.5 embryonic mouse brain, and cloned into pCAG-MCS2-myc and pCAG-MCS2-GFP vectors [14]. To generate an RNAi vector pSuperMacroD2, a MacroD2 target sequence (CTAGAAGTT-GACTTCAAAA, 673-691) was inserted into pSuper-puro (OligoEngine, Seattle, WA, USA).…”