Asxl1 loss in mice leads to microcephaly by regulating neural stem cell survival DOI Creative Commons

Hyeju Kim,

A.-Reum Kim,

Sukyoung Byun

и другие.

Animal Cells and Systems, Год журнала: 2025, Номер 29(1), С. 241 - 250

Опубликована: Апрель 23, 2025

Additional sex comb-like 1 (ASXL1) is a chromatin-associated factor essential for transcriptional regulation. De novo truncating mutations in the ASXL1 gene are linked to Bohring-Opitz syndrome, developmental disorder characterized by microcephaly; however, role of Asxl1 brain development remains unclear. In this study, we demonstrate that deletion mice induces microcephaly, primarily caused reduction size and number cortical neurons. ablation disrupts neural stem cell (NSC) maintenance, as evidenced decreased proliferation increased apoptosis. Transcriptomic analysis Asxl1-deficient NSCs revealed 4,635 differentially expressed genes, including 2,262 upregulated 2,373 downregulated genes. Gene ontology indicated regulates NSC survival through histone methyltransferase Ezh2, core component Polycomb Repressive Complex 2 (PRC2). Inhibition H3K27me3 using GSK343 significantly reduced viability wild-type NSCs, but had markedly diminished effect on NSCs. Furthermore, Ezh2 target genes associated with apoptosis, such Epha7 Osr1, were following treatment not affected These findings establish critical regulator neurogenesis via Ezh2-mediated chromatin modification provide insights into mechanisms underlying microcephaly disorders.

Язык: Английский

Asxl1 loss in mice leads to microcephaly by regulating neural stem cell survival DOI Creative Commons

Hyeju Kim,

A.-Reum Kim,

Sukyoung Byun

и другие.

Animal Cells and Systems, Год журнала: 2025, Номер 29(1), С. 241 - 250

Опубликована: Апрель 23, 2025

Additional sex comb-like 1 (ASXL1) is a chromatin-associated factor essential for transcriptional regulation. De novo truncating mutations in the ASXL1 gene are linked to Bohring-Opitz syndrome, developmental disorder characterized by microcephaly; however, role of Asxl1 brain development remains unclear. In this study, we demonstrate that deletion mice induces microcephaly, primarily caused reduction size and number cortical neurons. ablation disrupts neural stem cell (NSC) maintenance, as evidenced decreased proliferation increased apoptosis. Transcriptomic analysis Asxl1-deficient NSCs revealed 4,635 differentially expressed genes, including 2,262 upregulated 2,373 downregulated genes. Gene ontology indicated regulates NSC survival through histone methyltransferase Ezh2, core component Polycomb Repressive Complex 2 (PRC2). Inhibition H3K27me3 using GSK343 significantly reduced viability wild-type NSCs, but had markedly diminished effect on NSCs. Furthermore, Ezh2 target genes associated with apoptosis, such Epha7 Osr1, were following treatment not affected These findings establish critical regulator neurogenesis via Ezh2-mediated chromatin modification provide insights into mechanisms underlying microcephaly disorders.

Язык: Английский

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