Laboratory of Molecular Neuro-oncology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell Rep. 2023 Feb 28;42(2):112050. doi: 10.1016/j.celrep.2023.112050. Epub 2023 Jan 29.
We describe a patient haploinsufficient for the neuronal RNA binding protein NOVA1 who developed a behavioral motor hyperactivity disorder, suggesting a role of NOVA1 in postnatal motor inhibition. To investigate Nova1's action in adult Gad2 inhibitory neurons, we generated a conditional Nova1-null mouse (Nova1-cKO). Strikingly, the phenotypes of these mice show many similarities to the NOVA1 haploinsufficient patient and identify a function of Nova1 in the hypothalamus. Molecularly, Nova1 loss in Gad2-positive neurons alters downstream expression of Impact mRNA, along with a subset of RNAs encoding electron transport chain-related factors and ribosomal proteins. NOVA1 stabilizes Impact mRNA by binding its 3' UTR, antagonizing the actions of miR-138 and miR-124. Together, these studies demonstrate actions of NOVA1 in adult hypothalamic neurons, mechanisms by which it functions in translation and metabolism, including through direct binding to Impact mRNA, and illuminate its role in human neurologic disease.
我们描述了一位 NOVA1 神经元 RNA 结合蛋白单倍不足的患者，该患者出现了行为运动亢进障碍，提示 NOVA1 在出生后运动抑制中的作用。为了研究 Nova1 在成年 Gad2 抑制性神经元中的作用，我们生成了条件性 Nova1 敲除小鼠（Nova1-cKO）。引人注目的是，这些小鼠的表型与 NOVA1 单倍不足的患者非常相似，确定了 Nova1 在下丘脑的功能。从分子角度来看，Gad2 阳性神经元中的 Nova1 缺失改变了 Impact mRNA 的下游表达，以及一组编码电子传递链相关因子和核糖体蛋白的 RNA。NOVA1 通过结合其 3'UTR 稳定 Impact mRNA，拮抗 miR-138 和 miR-124 的作用。总之，这些研究表明 NOVA1 在成年下丘脑神经元中的作用，以及它在翻译和代谢中的作用机制，包括通过直接结合 Impact mRNA，并阐明了它在人类神经疾病中的作用。
