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Tajima, Yoko; Ito, Keiichi; Yuan, Yuan; Frank, Mayu O.; Saito, Yuhki; Darnell, Robert B.
Cell reports (Cambridge), 02/2023, Volume: 42, Issue: 2Journal Article
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-cKOGad2-cre). 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. Display omitted •NOVA1 haploinsufficiency impairs motor inhibition behavior and learning in humans•Nova1 deletion in Gad2+ neurons causes abnormalities referable to the hypothalamus•NOVA1 regulates translation- and electron transport chain-related gene expression•NOVA1 stabilizes Impact mRNA via 3′ UTR binding and miRNA competition Tajima et al. report that NOVA1 regulates motor inhibition and learning in humans. NOVA1 acts on Gad2+ neurons in the mouse hypothalamus, regulating physiology and behavior. Molecularly, NOVA1 stabilizes Impact mRNA through 3′ UTR binding, antagonizing miRNA binding, resulting in translational controls and effects on intracellular and systemic energy homeostasis.
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