Impaired Dendritic Development and Memory in<i>Sorbs2</i>Knock-Out Mice

Zhang, Qiangge; Xian, Gao; Li, Chenchen; Feliciano, Cátia; Wang, Dongqing; Zhou, Decheng; Yuan, Man; Monteiro, Patrícia; Anand, Michelle; Itohara, Shigeyoshi; Dong, Xiaowei; Fu, Zhanyan; Feng, Guoping

doi:10.1523/jneurosci.2528-15.2016

Cited by 62 publications

(60 citation statements)

References 66 publications

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“…While our manuscript was under revision, a study on the genetic ablation of Sorbs2 (nArgBP2) in mice was published that showed the reduction of dendritic complexity and excitatory synaptic transmission (22). Unlike our data, Sorbs2 knockout mice did not show significant alterations in dendritic spines.…”

Section: Methodscontrasting

confidence: 78%

“…nArgBP2 knockout mice show manic/bipolar-like behavior resembling many aspects of BD (22,23). The prefrontal cortex, striatum, and amygdala have been implicated in the pathogenesis of the disease (21,36), all of which are brain regions that express nArgBP2 highly (20).…”

Section: Discussionmentioning

confidence: 99%

“…deletion of nArgBP2 in mice leads to manic/bipolar-like behavior resembling many symptoms of BD (22,23). A recent study also showed that genetic deletion of SAPAP3, a binding partner of nArgBP2, causes anxiety-like behaviors in mice, thus implicating it in the pathogenesis of obsessive-compulsive behaviors (24).…”

Section: Significancementioning

confidence: 99%

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nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology

Lee

Kim

Han

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapseassociated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spinesynapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott-Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21-activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder. nArgBP2 | dendritic spines | excitatory synapse | actin | bipolar disorder T he postsynaptic enriched adaptor protein neural Abelsonrelated gene-binding protein 2 (nArgBP2), a neural-specific splice variant of the ubiquitous ArgBP2, was originally identified as a binding partner of synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) (1). It belongs to a family of adaptor proteins that are involved in the regulation of cell adhesion, actin cytoskeleton organization, and growth factor receptor signaling (2). This protein family is characterized by a sorbin homology (SoHo) domain in the NH 2 -terminal region and three Src homology 3 (SH3) domains in the COOH-terminal region (3). Although the SoHo domain remains poorly characterized, the SH3 domains bind signaling protein kinases, the ubiquitin ligase, and protein involved in the regulation of focal adhesions and adhering junctions (1, 4-6). The NH 2 -terminal region of nArgBP2, which contains the SoHo domain, interacts with spectrin, whereas the COOH-terminal SH3 domains bind dynamin, synaptojanin, Wiskott-Aldrich syndrome protein-family verprolin homologous protein (WAVE) isoforms, and WAVE regulatory proteins (3), all of which participate in the regulation of the actin cytoskeleton. We also found that the down-re...

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Section: Methodscontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology

Lee

Kim

Han

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Here, we examined whether Shank3 deletion differentially affected spine density in D1 MSNs versus D2 MSNs. We applied a modified viral-based method to sparsely label striatal neurons using a membrane-targeted EGFP (EGFPf) delivered with an AAV viral vector (AAV-hSyn1-EGFPf-WPRE-hGH), which could pass the blood-brain barrier to infect neurons when injected into the retroorbital venous sinus (77). We injected AAV-hSyn1-EGFPf-WPRE-hGH into 2-to 4-month-old Shank3B-KO/Drd1a-tdTomato and WT/Drd1a-tdTomato mice and imaged MSNs (Supplemental Figure 6).…”

Section: Resultsmentioning

confidence: 99%

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

Wang¹,

Li²,

Chen³

et al. 2017

Journal of Clinical Investigation

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“…Third, expression of SORBS2 protein was found to be significantly increased in the sera of patients with acute myocardial infarction, but depleted in the infarcted myocardia 24 . However, in vivo cardiac phenotypes have not been reported in a Sorbs2 knock-out (KO) mouse model 25 .…”

Section: Introductionmentioning

confidence: 99%

SORBS2is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

Ding

Yang

Chen

et al. 2019

Preprint

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BACKGROUND: Arrhythogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by right ventricular remodeling and ventricular arrhythmia. To date, 16 ARVC causative genes have been identified from human genetic studies, accounting for about 60% of ARVC probands. Genetic basis for the remaining 40% ARVC probands remain elusive. METHODS:Prompted by a zebrafish mutagenesis screen that suggested the Sorbin and SH3 domain-containing 2 (SORBS2) ortholog as a candidate cardiomyopathy gene, we conducted detailed expressionl analysis of Sorbs2 in mice, as well as phenotypic characterization in the Sorbs2 knock-out (KO) mice. The intercalated disc (ICD) expression pattern and ARVC-like phenotypes further prompted us to conduct targeted sequencing of human patients with ARVC to search for rare variants in the SORBS2 gene. RESULTS:Sorbs2 is robustly expressed in the mouse heart, encoding an adhesion junction/desmosome protein that is mainly localized to the ICD. A mutation with near complete depletion of the Sorbs2 protein in mouse results in phenotypes characteristic of human ARVC, such as dilated right ventricle (RV), RV dysfunction, spontaneous ventricular tachycardia (VT), and premature death. Sorbs2 is required to maintain the structural integrity of ICD. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Five rare variants were identified from a cohort of 59 ARVC patients, among which two variants affect splicing. CONCLUSIONS:Sorbs2 KO mouse is an ARVC model and SORBS2 is a new ARVC susceptibility gene.

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Impaired Dendritic Development and Memory inSorbs2Knock-Out Mice

Cited by 62 publications

References 66 publications

nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology

nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

SORBS2is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

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