Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, 44195, USA.
Nat Commun. 2024 Mar 28;15(1):2716. doi: 10.1038/s41467-024-47042-9.
Neural stem and progenitor cell (NSPC) maintenance is essential for ensuring that organisms are born with proper brain volumes and head sizes. Microcephaly is a disorder in which babies are born with significantly smaller head sizes and cortical volumes. Mutations in subunits of the DNA organizing complex condensin have been identified in microcephaly patients. However, the molecular mechanisms by which condensin insufficiency causes microcephaly remain elusive. We previously identified conserved roles for condensins in repression of retrotransposable elements (RTEs). Here, we show that condensin subunit knockdown in NSPCs of the Drosophila larval central brain increases RTE expression and mobility which causes cell death, and significantly decreases adult head sizes and brain volumes. These findings suggest that unrestricted RTE expression and activity may lead to improper brain development in condensin insufficient organisms, and lay the foundation for future exploration of causative roles for RTEs in other microcephaly models.
神经干细胞和祖细胞 (NSPC) 的维持对于确保生物体具有适当的大脑体积和头部大小至关重要。小头畸形是一种婴儿出生时头部大小和皮质体积明显较小的疾病。小头畸形患者中已经鉴定出 DNA 组织复合物凝聚素亚基的突变。然而，凝聚素不足导致小头畸形的分子机制仍然难以捉摸。我们之前发现凝聚素在抑制逆转录转座元件 (RTE) 方面具有保守作用。在这里，我们表明 Drosophila 幼虫中枢脑 NSPC 中的凝聚素亚基敲低会增加 RTE 的表达和迁移，从而导致细胞死亡，并显著降低成年期头部大小和大脑体积。这些发现表明，不受限制的 RTE 表达和活性可能导致凝聚素不足的生物体中大脑发育不正常，并为未来在其他小头畸形模型中探索 RTE 因果作用奠定了基础。
