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Autism-linked Cullin3 germline haploinsufficiency severely impacts mouse brain development and cortical neurogenesis through RhoA signaling

ABSTRACT: E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Neurodevelopmental Disorders such as Autism Spectrum Disorder (ASD) and Developmental Delay (DD). This study identifies the impact of the ASD-associated de novo Cul3-mutation on brain anatomy, behavior, molecular, cellular, and circuit-level mechanisms during early neocortical development. We report that Cul3 mutant mice have microcephaly and severe brain structure defects. This mouse model exhibits social and cognitive deficits and hyperactivity behavior. Spatiotemporal transcriptomic and proteomic profiling of Cul3 mouse brain implicates neurogenesis and cytoskeletal defects as key drivers of Cul3 functional effect. We show that Cul3 is critical for neuron growth and development. Cultured cortical neurons from the mutant mice have reduced dendritic length, actin cytosketon defects, reduced network activity, and increased cell death. At the molecular level, we implicate upregulation of small GTPase RhoA, involved in regulation of cytoskeletal dynamics, and neurite outgrowth as one of the pathways impacted by the de novo Cul3 mutations in ASD. Treatment with small molecule RhoA inhibitor Rhosin rescues dendrite length phenotype and implicates RhoA pathway in ASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE144046 | GEO | 2021/03/16

REPOSITORIES: GEO

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Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

Project description:E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for neurodevelopmental disorders including autism spectrum disorder (ASD) and developmental delay (DD). We generated Cul3-haploinsufficient mouse model to investigate brain anatomy, behavior, molecular, cellular, and circuit-level mechanisms dysregulated by Cul3 mutations. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Quantitative proteomic profiling was performed by Tandem Mass Tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis with SPS-MS3 workflow.

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