PDF(Pubmed)
Abstract：
Neurodevelopmental disorders (NDDs) are a class of pathologies arising from perturbations in brain circuit formation and maturation with complex etiological triggers often classified as environmental and genetic. Neuropsychiatric conditions such as autism spectrum disorders (ASD), intellectual disability (ID), and attention deficit hyperactivity disorders (ADHD) are common NDDs characterized by their hereditary underpinnings and inherent heterogeneity. Genetic risk factors for NDDs are increasingly being identified in non-coding regions and proteins bound to them, including transcriptional regulators and chromatin remodelers. Importantly, de novo mutations are emerging as important contributors to NDDs and neuropsychiatric disorders. Recently, de novo mutations in transcriptional co-factor Zmiz1 or its regulatory regions have been identified in unrelated patients with syndromic ID and ASD. However, the role of Zmiz1 in brain development is unknown. Here, using publicly available databases and a Zmiz1 mutant mouse model, we reveal that Zmiz1 is highly expressed during embryonic brain development in mice and humans, and though broadly expressed across the brain, Zmiz1 is enriched in areas prominently impacted in ID and ASD such as cortex, hippocampus, and cerebellum. We investigated the relationship between Zmiz1 structure and pathogenicity of protein variants, the epigenetic marks associated with Zmiz1 regulation, and protein interactions and signaling pathways regulated by Zmiz1. Our analysis reveals that Zmiz1 regulates multiple developmental processes, including neurogenesis, neuron connectivity, and synaptic signaling. This work paves the way for future studies on the functions of Zmiz1 and highlights the importance of combining analysis of mouse models and human data.
摘要：
神经发育障碍（NDD）是一类由脑回路形成和成熟的扰动引起的病理，具有复杂的病因触发因素，通常分为环境和遗传。神经精神疾病，如自闭症谱系障碍（ASD），智力残疾（ID），注意缺陷多动障碍（ADHD）是常见的NDD，其特征是遗传基础和固有异质性。NDD的遗传风险因素越来越多地在非编码区和与之结合的蛋白质中被识别出来，包括转录调节因子和染色质重塑因子。重要的是,从头突变正在成为NDD和神经精神疾病的重要贡献者。最近,已在不相关的ID和ASD综合征患者中鉴定出转录辅因子Zmiz1或其调节区的从头突变。然而,Zmiz1在大脑发育中的作用是未知的。这里,使用公开可用的数据库和Zmiz1突变小鼠模型，我们发现Zmiz1在小鼠和人类的胚胎脑发育过程中高度表达，尽管在整个大脑中广泛表达，Zmiz1富含在ID和ASD中受到显著影响的区域，如皮质，海马体,还有小脑.我们研究了Zmiz1结构与蛋白质变体的致病性之间的关系，与Zmiz1调节相关的表观遗传标记，以及Zmiz1调控的蛋白质相互作用和信号通路。我们的分析表明，Zmiz1调节多个发育过程，包括神经发生，神经元连通性，和突触信号。这项工作为将来研究Zmiz1的功能铺平了道路，并强调了将小鼠模型和人类数据分析相结合的重要性。
