Alternative splicing variations in mouse CAPS2: differential expression and functional properties of splicing variants

Sadakata, Tetsushi; Washida, Miwa; Furuichi, Teiichi

doi:10.1186/1471-2202-8-25

Cited by 28 publications

(30 citation statements)

References 19 publications

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“…1F). This supported our hypothesis that full-length Caps2 protein [exon3-plus; the dominant form in mouse (27) and human (8) brains] can be transported into axons, whereas dex3 protein (exon3-minus) cannot (8). In the wild-type mouse hippocampus, Caps2 protein was expressed in dentate gyrus (DG) granule cells and cornu ammonis region 1 (CA1) pyramidal neurons in addition to a subset of interneurons scattered in the DG and CA1 regions (28), as shown in Fig.…”

Section: Generation Of a Mouse Line Expressing Exon 3-skipped Caps2 (supporting

confidence: 78%

Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice

Sadakata

Shinoda

Oka

et al. 2012

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

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Ca 2+-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Here, we generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in socialand anxiety-related behaviors. Together, these findings represent a unique mouse model of a molecular mechanism linking BDNFmediated coordination of brain development to autism-related behaviors and patient genotype.-dependent activator protein for secretion 2 (CAPS2 or CADPS2) is a member of the CAPS protein family that regulates the trafficking of dense-core vesicles by binding both phosphoinositides and dense-core vesicles (1-5). We initially identified mouse Caps2 as a potent factor promoting the release of brain-derived neurotrophic factor (BDNF) during cerebellar development (6, 7). Our subsequent knockout mouse study showed that Caps2 not only plays a role in neuronal development of the cerebrum and hippocampus as well as the cerebellum, but that it is also associated with social interaction, anxiety, and maternal and circadian behaviors in mice (7,8). We also showed that the expression of an exon 3-skipped (or -spliced out) form of CAPS2 (designated CAPS2-dex3) (8), which is now known to be a rare alternative splicing variant (9, 10), is increased in a subgroup of patients with autism and is not properly localized in axons (8). Thus, neurons overexpressing dex3 may fail to coordinate local BDNF release from axons properly (8, 9), resulting in improper brain development and function. The human CAPS2 gene locus (7q31.32) is intriguingly located within the autism susceptibility locus 1 (AUTS1) (11) on chromosome 7q31-q33, one of several susceptibility loci for autism (12). Moreover, an association of CAPS2 with autism has been suggested recently, not only by the presence of copy number variations in the CAPS2 gene in autistic patients (13-15), but also by decreased transcription of CAPS2 in the brains of people with autism (16). Thus, clarifying the biological significance of dex3 expression is an important step in elucidating the association of CAPS2 with brain circuit development and behaviors related to autism.The potential molecular risk factors for autism susceptibility have been increasingly reported (17-26) but are poorly characterized in animal models. In this report, we generated a mouse model expressing dex3 and analyzed the cellular and autistic-like behavioral phenotypes of dex3 mice. Our results support the involvement of the rare dex3 form of Caps2 in defective axonal BDNF secretion, affecting proper brain circuit development and/ or functio...

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Section: Generation Of a Mouse Line Expressing Exon 3-skipped Caps2 (supporting

confidence: 78%

Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice

Sadakata

Shinoda

Oka

et al. 2012

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

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“…The three short splice variants CAPS2d-CAPS2f all contain a unique C terminus, while the N-terminal sequence of all six splice variants is identical. (Sadakata et al, 2007). Domains are as follows: DID, C2 domain, PH domain, MUN domain.…”

Section: Resultsmentioning

confidence: 99%

“…We examined the functionality of six naturally occurring splice variants of CAPS2 (Sadakata et al, 2007) by assessing their ability to reverse the profound secretory deficits of CAPS1/ CAPS2-deficient (CAPS1/CAPS2 DKO) chromaffin cells and hippocampal neurons. Two of these splice variants, CAPS2a and CAPS2b, contain all domains, but differ by the presence or absence of one exon in the MUN domain (exon 22; Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Secretory Vesicle Priming by CAPS Is Independent of Its SNARE-Binding MUN Domain

et al. 2014

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Priming of secretory vesicles is a prerequisite for their Ca(2+)-dependent fusion with the plasma membrane. The key vesicle priming proteins, Munc13s and CAPSs, are thought to mediate vesicle priming by regulating the conformation of the t-SNARE syntaxin, thereby facilitating SNARE complex assembly. Munc13s execute their priming function through their MUN domain. Given that the MUN domain of Ca(2+)-dependent activator protein for secretion (CAPS) also binds syntaxin, it was assumed that CAPSs prime vesicles through the same mechanism as Munc13s. We studied naturally occurring splice variants of CAPS2 in CAPS1/CAPS2-deficient cells and found that CAPS2 primes vesicles independently of its MUN domain. Instead, the pleckstrin homology domain of CAPS2 seemingly is essential for its priming function. Our findings indicate a priming mode for secretory vesicles. This process apparently requires membrane phospholipids, does not involve the binding or direct conformational regulation of syntaxin by MUN domains of CAPSs, and is therefore not redundant with Munc13 action.

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“…1c) with an expression peak around postnatal day (P)7-12 ( Fig. 1b) and is a BDNF release regulator that is potentially associated with autism [3,4,6,7]. Cupidin/Homer2 is predominantly expressed in early-stage GCs and is a postsynaptic density scaffold protein that tethers mGluR1α/5, inositol 1,4,5-trisphosphate receptor, and Shank [8,9].…”

Section: Identification Of Caps2 Via a Cerebellar Development Transcrmentioning

confidence: 98%

Developmentally Regulated Ca2+-Dependent Activator Protein for Secretion 2 (CAPS2) is Involved in BDNF Secretion and is Associated with Autism Susceptibility

Sadakata

Furuichi

2009

Cerebellum

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The postnatal development of the cerebellum is accomplished via a series of cytogenetic and morphogenetic events encoded in the genome. To decipher the underlying genetic basis of these events we have systematized the spatio-temporal gene expression profiles during mouse cerebellar development in the Cerebellar Development Transcriptome Database (CDT-DB). Using the CDT-DB, Ca(2+)-dependent activator protein for secretion 2 (CAPS2 or CADPS2) was identified as a developmentally regulated gene that is predominantly expressed in cerebellar granule cells (GCs) with an expression peak around the first or second postnatal week. CAPS2 protein is concentrated in parallel fiber (PF) terminals and is associated with secretory vesicles containing brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). CAPS2 enhances release of BDNF and NT-3, both of which are essential for normal cerebellar development. CAPS2-deficient (CAPS2(-/-)) mice show reduced secretion of BDNF and NT-3; consequently, the cerebella of these mice exhibit developmental deficits, such as delayed development and increased cell death in GCs, fewer branched dendrites on Purkinje cells (PCs), and loss of the intercrural fissure. The PF-PC synapses have aberrant cytoarchitectures and electrophysiological properties. These abnormal cellular and morphological phenotypes are more severe around the cerebellar vermis, in which hypoplasia has been reported in autism patients. Moreover, CAPS2(-/-) mice had fewer cortical and hippocampal parvalbumin-positive interneurons and some autistic-like behavioral phenotypes. In the CAPS2 genes of some autistic patients an aberrant splicing variant and non-synonymous SNPs have been identified. These recent studies implicate CAPS2 in autism susceptibility. Therefore, CAPS2(-/-) mice will be a useful model animal in which to study aspects of the neuropathology and behaviors characteristic of developmental disorders.

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Alternative splicing variations in mouse CAPS2: differential expression and functional properties of splicing variants

Cited by 28 publications

References 19 publications

Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice

Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice

Secretory Vesicle Priming by CAPS Is Independent of Its SNARE-Binding MUN Domain

Developmentally Regulated Ca2+-Dependent Activator Protein for Secretion 2 (CAPS2) is Involved in BDNF Secretion and is Associated with Autism Susceptibility

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