Ottawa Hospital Research Institute (OHRI), Ottawa, ON K1H 8L6, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Hum Mol Genet. 2023 Dec 1;32(24):3361-3373. doi: 10.1093/hmg/ddad157.
Chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), however, their functions during brain development are not fully understood. Here, we focused on Sifrim-Hitz-Weiss Syndrome (SIHIWES)-an intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. We utilized mouse genetics to excise the Chd4 ATPase/helicase domain-either constitutively, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited no change in cortical size and cellular composition, and had only subtle behavioral phenotypes. Telencephalon-specific conditional knockouts had marked reductions in cortical growth, reduced numbers of upper-layer neurons, and exhibited alterations in anxiety and repetitive behaviors. Despite the fact that whole-body heterozygotes exhibited comparable growth defects, they were unaffected in these behaviors, but instead exhibited female-specific alterations in learning and memory. These data reveal unexpected phenotypic divergence arising from differences in the spatiotemporal deployment of loss-of-function manipulations, underscoring the importance of context in chromatin remodeller function during neurodevelopment.
染色质重塑因子是与神经发育障碍（NDDs）相关的最重要的风险基因之一，然而，它们在大脑发育过程中的功能尚未完全了解。在这里，我们专注于 Sifrim-Hitz-Weiss 综合征（SIHIWES）——一种由 CHD4 染色质域螺旋酶基因突变引起的智力障碍疾病。我们利用小鼠遗传学技术，切除 Chd4 ATP 酶/解旋酶结构域，无论是在大脑皮质发育过程中持续地还是条件性地切除。条件性杂合子在皮质大小和细胞组成上没有变化，只有细微的行为表型。大脑皮质特异性条件性敲除鼠表现出皮质生长明显减少、上皮层神经元数量减少，并表现出焦虑和重复行为的改变。尽管全身性杂合子表现出类似的生长缺陷，但它们在这些行为上不受影响，而是表现出女性特异性的学习和记忆改变。这些数据揭示了由于功能丧失操作的时空部署差异而产生的出乎意料的表型分歧，强调了在神经发育过程中染色质重塑因子功能中背景的重要性。
