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. 3 samples

核受体Nr2f1是胚胎期与出生后神经细胞中强效的转录调控因子。在人类中，其突变会引发博世-邦斯特拉-沙夫视神经萎缩-智力障碍综合征（Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome，BBSOAS）——一种以视神经萎缩、智力障碍及自闭症特征等多种临床表型为特征的罕见神经发育障碍。本研究通过全基因组分析与计算机模拟分析（in silico），鉴定出大量核编码线粒体基因，可作为神经元中Nr2f1直接转录调控的潜在基因组靶点。结合小鼠遗传学、神经解剖学与影像学手段，我们证实成年小鼠海马神经发生微环境中条件性Nr2f1功能丧失，会导致新生神经元线粒体质量降低，伴随线粒体碎裂及关键线粒体蛋白表达下调，进而损害新生神经元的功能整合与存活能力。值得注意的是，在已被验证为BBSOAS模型的Nr2f1杂合子小鼠脑组织中，我们同样发现了多个线粒体基因表达失调以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活跃作用，同时支持线粒体功能异常参与BBSOAS的发病机制。本研究共纳入3份样本。