染色质重塑剂ADNP调节神经发育障碍风险基因和新皮质神经发生

IF 9.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Samuel Clémot-Dupont, José Alex Lourenço Fernandes, Sarah Larrigan, Xiaoqi Sun, Suma Medisetti, Rory Stanley, Ziyad El Hankouri, Shrilaxmi V. Joshi, David J. Picketts, Karthik Shekhar, Pierre Mattar
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引用次数: 0

摘要

尽管染色质重塑因子是与神经发育障碍(ndd)相关的最重要的风险基因之一,但在许多情况下,这些复合物在大脑发育中的作用尚不清楚。在这里,我们关注的是最近发现的ChAHP染色质重塑复合体。锌指和同源结构域转录因子ADNP是该复合体的核心亚基,ADNP突变可导致智力残疾和自闭症谱系障碍。然而,种系Adnp敲除小鼠先前显示出早期胚胎致死性,模糊了ChAHP复合物在神经发生中的后续作用。为了避免这种早期发育停滞,我们产生了一个条件Adnp突变等位基因。利用单细胞转录组学、cut - runseq和组织学方法,我们发现在新皮层发育过程中,Adnp通过两个步骤协调了晚生上层神经元的产生。首先,在上层皮层神经发生的发育窗口期,Adnp是维持祖细胞增殖所必需的。因此,我们发现Adnp将ChAHP亚基Chd4招募到与祖细胞增殖相关的基因中。其次,在有丝分裂后分化的神经元中,我们定义了一个由Adnp和Chd4调节的与ndd相关的风险基因网络。综上所述,这些数据表明ChAHP对于驱动上层皮质神经元的扩张和调节神经元基因表达程序至关重要,这表明这些过程可能有助于NDD的病因学。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The chromatin remodeler ADNP regulates neurodevelopmental disorder risk genes and neocortical neurogenesis
Although chromatin remodelers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodeling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, and de novo ADNP mutations lead to intellectual disability and autism spectrum disorder. However, germline Adnp knockout mice were previously shown to exhibit early embryonic lethality, obscuring subsequent roles for the ChAHP complex in neurogenesis. To circumvent this early developmental arrest, we generated a conditional Adnp mutant allele. Using single-cell transcriptomics, cut&run-seq, and histological approaches, we show that during neocortical development, Adnp orchestrates the production of late-born, upper-layer neurons through a two-step process. First, Adnp is required to sustain progenitor proliferation specifically during the developmental window for upper-layer cortical neurogenesis. Accordingly, we found that Adnp recruits the ChAHP subunit Chd4 to genes associated with progenitor proliferation. Second, in postmitotic differentiated neurons, we define a network of risk genes linked to NDDs that are regulated by Adnp and Chd4. Taken together, these data demonstrate that ChAHP is critical for driving the expansion of upper-layer cortical neurons and for regulating neuronal gene expression programs, suggesting that these processes may potentially contribute to NDD etiology.
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来源期刊
CiteScore
19.00
自引率
0.90%
发文量
3575
审稿时长
2.5 months
期刊介绍: The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.
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