A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation [RNA-Seq]. A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation [RNA-Seq]

Human genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. Studies during brain development reveal disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and highlight precocious neuronal differentiation as the mechanism for microcephaly. In contrast, adult studies reveal that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral features including hyperactivity, hypotonia, and social alterations, with more severe phenotypes in males. Overall, these studies provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies. Overall design: Utilizing MYT1L KO mouse line, we performed ATAC-seq and RNA-seq on developing mouse brain (E14.5 cortex) and adult prefrontal cortex to undertsand chromatin structure changes and transcriptom alternation upon MYT1L loss.

人类遗传学研究已明确了一种由MYT1L功能丧失性突变引发的全新自闭症相关综合征。MYT1L是一种已知可介导成纤维细胞向神经元转化的转录因子（transcription factor）。然而，MYT1L突变如何导致自闭症、注意缺陷多动障碍（ADHD）、智力障碍、肥胖及脑部异常，目前仍未明确。
本研究构建了该综合征的小鼠模型。在生理层面，Myt1l单倍体剂量不足（haploinsufficiency）可导致小鼠出现肥胖、白质稀疏及小头畸形，模拟了该综合征的临床表型。
脑发育阶段的研究发现，基因表达出现紊乱，该紊乱部分由Myt1l靶基因的激活缺失所介导；研究同时明确神经元过早分化是小头畸形的致病机制。
与之相反，成年小鼠的研究显示，MYT1L突变会导致转录与染色质成熟过程受阻，这与神经元基础生理特性紊乱的现象相一致。
这会引发多动、肌张力低下及社交行为改变等行为学特征，且雄性小鼠的表型更为严重。
综上，本研究揭示了该疾病的潜在致病机制，为后续临床前研究奠定了基础。
实验设计：本研究使用MYT1L敲除（KO，knockout）小鼠品系，对发育中小鼠大脑（胚胎14.5天皮层，E14.5 cortex）及成年前额叶皮层开展ATAC-seq与RNA-seq测序，以解析MYT1L缺失后染色质结构变化与转录组（transcriptome）改变。