Shank3a/b isoforms regulate the susceptibility to seizures and thalamocortical development in the early postnatal period of mice

Okuzono, Sayaka; Fujii, Fumihiko; Matsushita, Yuki; Setoyama, Daiki; Shinmyo, Yohei; Taira, Ryoji; Yonemoto, Kousuke; Akamine, Satoshi; Motomura, Yoshitomo; Sanefuji, Masafumi; Sakurai, Takeshi; Kawasaki, Hiroshi; Han, Ki-Hoon; Kato, Takahiro A.; Torisu, Hiroyuki; Kang, Dongchon; Nakabeppu, Yusaku; Sakai, Yasunari; Ohga, Shouichi

doi:10.1016/j.neures.2023.03.001

Cited by 5 publications

References 40 publications

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Deciphering the Role of Shank3 in Dendritic Morphology and Synaptic Function Across Postnatal Developmental Stages in the Shank3B KO Mouse

Yang,

Ma,

et al. 2024

Neurosci. Bull.

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Autism Spectrum Disorder (ASD) is marked by early-onset neurodevelopmental anomalies, yet the temporal dynamics of genetic contributions to these processes remain insufficiently understood. This study aimed to elucidate the role of the Shank3 gene, known to be associated with monogenic causes of autism, in early developmental processes to inform the timing and mechanisms for potential interventions for ASD. Utilizing the Shank3B knockout (KO) mouse model, we examined Shank3 expression and its impact on neuronal maturation through Golgi staining for dendritic morphology and electrophysiological recordings to measure synaptic function in the anterior cingulate cortex (ACC) across different postnatal stages. Our longitudinal analysis revealed that, while Shank3B KO mice displayed normal neuronal morphology at one week postnatal, significant impairments in dendritic growth and synaptic activity emerged by two to three weeks. These findings highlight the critical developmental window during which Shank3 is essential for neuronal and synaptic maturation in the ACC.

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Deciphering the Role of Shank3 in Dendritic Morphology and Synaptic Function Across Postnatal Developmental Stages in the Shank3B KO Mouse

Yang,

Ma,

et al. 2024

Neurosci. Bull.

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Convergence of autism proteins at the cilium

Kostyanovskaya,

Lasser,

Wang

et al. 2024

Preprint

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Hundreds of high-confidence autism genes have been identified, yet the relevant etiological mechanisms remain unclear. Gene ontology analyses have repeatedly identified enrichment of proteins with annotated functions in gene expression regulation and neuronal communication. However, proteins are often pleiotropic and these annotations are inherently incomplete. Our recent autism functional genetics work has suggested that these genes may share a common mechanism at the cilium, a membrane-bound organelle critical for neurogenesis, brain patterning, and neuronal activity-all processes strongly implicated in autism. Moreover, autism commonly co-occurs with conditions that are known to involve ciliary-related pathologies, including congenital heart disease, hydrocephalus, and blindness. However, the role of autism genes at the cilium has not been systematically investigated. Here we demonstrate that autism proteins spanning disparate functional annotations converge in expression, localization, and function at cilia, and that patients with pathogenic variants in these genes have cilia-related co-occurring conditions and biomarkers of disrupted ciliary function. This degree of convergence among genes spanning diverse functional annotations strongly suggests that cilia are relevant to autism, as well as to commonly co-occurring conditions, and that this organelle should be explored further for therapeutic potential.

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An N‐terminal and ankyrin repeat domain interactome of Shank3 identifies the protein complex with the splicing regulator Nono in mice

Okuzono,

Fujii,

Setoyama

et al. 2024

Genes to Cells

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An autism‐associated gene Shank3 encodes multiple splicing isoforms, Shank3a‐f. We have recently reported that Shank3a/b‐knockout mice were more susceptible to kainic acid‐induced seizures than wild‐type mice at 4 weeks of age. Little is known, however, about how the N‐terminal and ankyrin repeat domains (NT‐Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry‐based proteomic search for proteins interacting with GFP‐tagged NT‐Ank. In this study, NT‐Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA‐binding (n = 102), spliceosome (n = 22), and ribosome‐associated molecules (n = 9) were significantly enriched. Among them, an X‐linked intellectual disability‐associated protein, Nono, was identified as a NT‐Ank‐binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b‐knockout mice aberrantly expressed splicing isoforms of autism‐associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA‐binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism‐associated genes after birth.

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Shank3a/b isoforms regulate the susceptibility to seizures and thalamocortical development in the early postnatal period of mice

Cited by 5 publications

References 40 publications

Deciphering the Role of Shank3 in Dendritic Morphology and Synaptic Function Across Postnatal Developmental Stages in the Shank3B KO Mouse

Deciphering the Role of Shank3 in Dendritic Morphology and Synaptic Function Across Postnatal Developmental Stages in the Shank3B KO Mouse

Convergence of autism proteins at the cilium

An N‐terminal and ankyrin repeat domain interactome of Shank3 identifies the protein complex with the splicing regulator Nono in mice

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