Biology subjects

Egusa, S. F.

Publications and source records attributed to Egusa, S. F..

3 recordsLinked to original sources

bioRxiv2024

AUTS2, a causative gene for microcephaly, regulates division of intermediate progenitor cells and production of upper-layer neurons

AUTS2 mutations often exhibit neurodevelopmental disorders and microcephaly. However, how AUTS2 regulates neuron production and affects brain size remains unclear. Here, we show that AUTS2 cooperates with the Polycomb complex PRC2 to regulate gene expression and cortical neurogenesis. Auts2 mutant mice exhibit reduced division of intermediate progenitor cells (IPCs), leading to decreased neurons and thickness in the upper-layer cortex. Expression of Robo1 is increased in the mutants, which in turn suppresses IPC division. Transcriptome and chromatin profiling experiments show that, in IPCs, AUTS2 primarily represses transcription of genes, including Robo1. Promoter region of AUTS2 target genes is enriched with H3K27me3, a repressive histone modification, but its levels are reduced in Auts2 mutants. AUTS2 interacts with PRC2, and together, they promote IPC division. These suggest that AUTS2 collaborates with PRC2 to repress gene transcription through H3K27 trimethylation, promoting neuron production. This sheds light on AUTS2 pathophysiological mechanisms in neurogenesis and microcephaly.

neuroscience↗

bioRxiv2020

AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication

Autism susceptibility candidate 2 (AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development. Auts2 conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression of Cacna1a. Auts2 cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses, and restriction of parallel fiber synapse numbers. Auts2 cKO mice exhibited behavioral impairments in motor learning and vocal communications. Because Cacna1a is known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment of AUTS2 may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs.

neuroscience↗

bioRxiv2019

AUTS2 regulation of synapses for proper synaptic inputs and social communication.

Impairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2-deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.

neuroscience↗