Nr2f1-dependent shaping of mitochondrial architecture in newborn mouse hippocampal neurons unravels novel insights into the neurodevelopmental disorder BBSOAS

The nuclear receptor Nr2f1, also known as COUP-TFI, plays a key role during cortical development by acting as a strong transcriptional regulator in embryonic and adult neural cells. In humans, NR2F1 mutations cause the Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including optic nerve atrophy, cerebral visual impairment, seizures, intellectual disability, and autistic traits. Moreover, alterations in mitochondrial energy supply have been recently reported in some BBSOAS patients. Although mitochondrial dysfunction is increasingly implicated in neurodevelopmental disorders, whether and how Nr2f1 can regulate mitochondria function in neural cells is still completely unknown. To address these questions, we have combined genome-wide and in silico analyses with mouse genetics, neuroanatomical and imaging approaches. First, we found that key factors for mitochondrial function and dynamics represent potential genomic targets under direct Nr2f1 transcriptional control in neurons. To genetically manipulate Nr2f1 function in a restricted neuronal population, we focused on the adult mouse hippocampal dentate gyrus, a site of persistent neurogenesis in rodents and where Nr2f1 is highly expressed. We showed that both loss- and gain-of-function of Nr2f1 within the hippocampal neurogenic niche led to altered mitochondrial architecture in newborn neurons likely reflecting alteration in mitochondrial dynamics. Lastly, we identified the fusion factor Mfn2 as a putative Nr2f1 target and demonstrated its downregulation following both Nr2f1 adult depletion and embryonic haploinsufficiency in mice. Overall, our study provides the first evidence of a significant role of Nr2f1 in shaping mitochondrial architecture in neurons and opens a promising avenue for the identification of new mechanisms implicated in BBSOAS pathogenesis involving mitochondrial dysfunction. ### Competing Interest Statement The authors have declared no competing interest.