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

被引:0
作者
Kim, Hyeju [1 ]
Kim, A. -Reum [1 ]
Byun, Sukyoung [1 ]
Um, Soo-Jong [1 ]
机构
[1] Sejong Univ, Dept Integrat Biosci & Biotechnol, 209 Neungdong ro, Seoul 05006, South Korea
关键词
Additional sex comb-like1 (Asxl1); Bohring-Opitz Syndrome (BOS); microcephaly; neural stem cells (NSCs); Ezh2; BOHRING-OPITZ-SYNDROME; RADIAL GLIAL-CELLS; RECIPROCAL REGULATION; NEURONS ARISE; LXR-ALPHA; BRAIN; PROLIFERATION; MUTATIONS; APOPTOSIS; FAMILY;
D O I
10.1080/19768354.2025.2481979
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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, a developmental disorder characterized by microcephaly; however, the role of Asxl1 in brain development remains unclear. In this study, we demonstrate that Asxl1 deletion in mice induces microcephaly, primarily caused by a reduction in the size and number of cortical neurons. Asxl1 ablation disrupts neural stem cell (NSC) maintenance, as evidenced by decreased proliferation and increased apoptosis. Transcriptomic analysis of Asxl1-deficient NSCs revealed 4,635 differentially expressed genes, including 2,262 upregulated and 2,373 downregulated genes. Gene ontology analysis indicated that Asxl1 regulates NSC survival through the histone methyltransferase Ezh2, a core component of the Polycomb Repressive Complex 2 (PRC2). Inhibition of H3K27me3 using GSK343 significantly reduced the viability of wild-type NSCs, but had a markedly diminished effect on Asxl1-deficient NSCs. Furthermore, Ezh2 target genes associated with apoptosis, such as Epha7 and Osr1, were upregulated in wild-type NSCs following GSK343 treatment but not significantly affected in Asxl1-deficient NSCs. These findings establish Asxl1 as a critical regulator of NSC survival and neurogenesis via Ezh2-mediated chromatin modification and provide insights into the mechanisms underlying microcephaly in developmental disorders.
引用
收藏
页码:241 / 250
页数:10
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