BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE199327 | GEO | 2022/06/08
REPOSITORIES: GEO
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Project description:BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination
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Project description:Although mechanisms underlying early steps in cerebellar development are known, evidence is lacking on genetic and epigenetic changes during the establishment of the synaptic circuitry. Using metagene analysis, we report pivotal changes in multiple reactomes of epigenetic pathway genes in cerebellar granule cells (GCs) during circuit formation. During this stage, Tet genes are up-regulated and vitamin C activation of Tet enzymes increases the levels of 5-hydroxymethylcytosine (5hmC) at exon start sites of up-regulated genes, notably axon guidance genes and ion channel genes. Knockdown of Tet1 and Tet3 by RNA interference in ex vivo cerebellar slice cultures inhibits dendritic arborization of developing GCs, a critical step in circuit formation. These findings demonstrate a role for Tet genes and chromatin remodeling genes in the formation of cerebellar circuitry. 5hmC-enriched genomic DNA fragments were purified with a selective labeling strategy known as hMe-Seal and carried out DNA deep sequencing using Illumina HiSeq 2500.
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Project description:Transcriptome analysis of mRNA samples purified from developing cerebellar granule cells and ES cell-derived granule cells using translating ribosome affinity purification (TRAP) method. Although mechanisms underlying early steps in cerebellar development are known, evidence is lacking on genetic and epigenetic changes during the establishment of the synaptic circuitry. Using metagene analysis, we report pivotal changes in multiple reactomes of epigenetic pathway genes in cerebellar granule cells (GCs) during circuit formation. During this stage, Tet genes are up-regulated and vitamin C activation of Tet enzymes increases the levels of 5-hydroxymethylcytosine (5hmC) at exon start sites of up-regulated genes, notably axon guidance genes and ion channel genes. Knockdown of Tet1 and Tet3 by RNA interference in ex vivo cerebellar slice cultures inhibits dendritic arborization of developing GCs, a critical step in circuit formation. These findings demonstrate a role for Tet genes and chromatin remodeling genes in the formation of cerebellar circuitry.
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Project description:Astrotactin 2 (ASTN2) is a transmembrane, neuronal protein that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenic ASTN2 duplication, with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study ASTN2 role in cerebellar circuit function, we generated global and Purkinje cell-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization (USV) calls, increased hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Increased hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrates a large increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous EPSCs, as well as increased amplitudes of both spontaneous EPSCs and IPSCs in the Astn2 KO animals, suggesting that pre- and post-synaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
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