Nr2f1 shapes mitochondria in the mouse brain unraveling novel insights into the neurodevelopmental disorder BBSOAS. Nr2f1 shapes mitochondria in the mouse brain unraveling novel insights into the neurodevelopmental disorder BBSOAS

The nuclear receptor Nr2f1 acts as a strong transcriptional regulator in embryonic and postnatal neural cells. In humans, its mutations cause the Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including optic nerve atrophy, intellectual disability, and autistic traits. In this study, by genome-wide and in silico analyses we identified a wide set of nuclear-encoded mitochondrial genes as potential genomic targets under direct Nr2f1 transcriptional control in neurons. By combining mouse genetics, neuroanatomical and imaging approaches we demonstrated that conditional Nr2f1 loss-of-function within the adult mouse hippocampal neurogenic niche results in a reduced mitochondrial mass associated with mitochondrial fragmentation and downregulation of key mitochondrial proteins in newborn neurons, whose functional integration and survival are impaired. Importantly, we also found dysregulation of several mitochondrial genes and downregulation in levels of key mitochondrial proteins in the brain of mice heterozygous for Nr2f1, a validated BBSOAS model. Our data point to an active role of Nr2f1 in the mitochondrial gene expression regulatory network in neurons and support the involvement of mitochondrial dysfunction in BBSOAS pathogenesis. Overall design: 3 samples

核受体Nr2f1（nuclear receptor Nr2f1）是胚胎期与出生后神经细胞内的强效转录调控因子。在人类中，该基因的突变可引发Bosch-Boonstra-Schaaf视神经萎缩-智力综合征（Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome, BBSOAS）——一种以视神经萎缩、智力障碍及自闭症样特征为主要临床表型的罕见神经发育障碍疾病。本研究通过全基因组分析与计算机模拟分析，在神经元中鉴定出一大批受Nr2f1直接转录调控的核编码线粒体基因候选靶点。结合小鼠遗传学、神经解剖学与成像技术手段，本研究证实：成年小鼠海马神经发生微环境中Nr2f1的条件性功能缺失，会导致新生神经元出现线粒体质量降低、线粒体碎片化及关键线粒体蛋白表达下调，其功能整合与存活能力均受到损伤。值得关注的是，本研究还在Nr2f1杂合子小鼠（经验证的BBSOAS疾病模型）的脑组织中，发现多个线粒体基因表达失调及关键线粒体蛋白水平下调的现象。本研究数据表明，Nr2f1在神经元线粒体基因表达调控网络中发挥主动调控作用，并支持线粒体功能异常参与BBSOAS发病机制这一观点。实验整体设计：3个样本。