Nr2f1 controls mitochondrial dynamics in mouse adult-born hippocampal neurons
Nr2f1 controls mitochondrial dynamics in mouse adult-born hippocampal neurons
Abstract The nuclear receptor Nr2f1 plays a key role during cortical development by acting 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 found that key factors for mitochondrial function and dynamics represent potential genomic targets under direct Nr2f1 transcriptional control in neurons. 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 mouse genetics, neuroanatomical and imaging approaches. To genetically manipulate Nr2f1 function in newborn neurons we focused on the adult mouse hippocampal dentate gyrus, a site of persistent neurogenesis where Nr2f1 is highly expressed. We showed that conditional Nr2f1 loss-of-function within the hippocampal neurogenic niche lead to a reduced mitochondrial mass associated to mitochondrial fragmentation in newborn neurons, likely reflecting alteration in mitochondrial dynamics. Accordingly, we showed that the fusion factor Mfn2, which is as a putative Nr2f1 target, is downregulated following both Nr2f1 adult depletion and embryonic haploinsufficiency in mice. Overall, our study provides the first evidence of a crucial role of Nr2f1 in shaping mitochondria in neurons and opens a promising avenue for the identification of new mechanisms implicated in BBSOAS pathogenesis involving mitochondrial dysfunction.
Filippo Michelon、Isabella Crisci、Ivan Molineris、Francesco Neri、Serena Bovetti、Mich¨¨le Studer、Silvia De Marchis、Salvatore Oliviero、Paolo Peretto、Ruth Beckervordersandforth、Chichung Lie Dieter、Sara Bonzano
Department of Life Sciences and Systems Biology (DBIOS), University of Turin||Neuroscience Institute Cavalieri Ottolenghi (NICO)Department of Life Sciences and Systems Biology (DBIOS), University of Turin||Neuroscience Institute Cavalieri Ottolenghi (NICO)Department of Life Sciences and Systems Biology (DBIOS), University of Turin||IIGM Foundation-Italian Institute for Genomic MedicineDepartment of Life Sciences and Systems Biology (DBIOS), University of Turin||IIGM Foundation-Italian Institute for Genomic MedicineDepartment of Life Sciences and Systems Biology (DBIOS), University of Turin||Neuroscience Institute Cavalieri Ottolenghi (NICO)Institute de Biologie Valrose (iBV), Universit¨| C?te d?ˉAzur (UCA), CNRS 7277Department of Life Sciences and Systems Biology (DBIOS), University of Turin||Neuroscience Institute Cavalieri Ottolenghi (NICO)Department of Life Sciences and Systems Biology (DBIOS), University of Turin||IIGM Foundation-Italian Institute for Genomic MedicineDepartment of Life Sciences and Systems Biology (DBIOS), University of Turin||Neuroscience Institute Cavalieri Ottolenghi (NICO)Institut f¨1r Biochemie, Friedrich-Alexander Universit?t Erlangen-N¨1rnberg (FAU)Institut f¨1r Biochemie, Friedrich-Alexander Universit?t Erlangen-N¨1rnberg (FAU)Department of Life Sciences and Systems Biology (DBIOS), University of Turin||Neuroscience Institute Cavalieri Ottolenghi (NICO)
神经病学、精神病学基础医学分子生物学
COUP-TFImitochondriadentate gyrusneurogenesisadult-born neuronsMfn2
Filippo Michelon,Isabella Crisci,Ivan Molineris,Francesco Neri,Serena Bovetti,Mich¨¨le Studer,Silvia De Marchis,Salvatore Oliviero,Paolo Peretto,Ruth Beckervordersandforth,Chichung Lie Dieter,Sara Bonzano.Nr2f1 controls mitochondrial dynamics in mouse adult-born hippocampal neurons[EB/OL].(2025-03-28)[2025-07-19].https://www.biorxiv.org/content/10.1101/2022.03.25.485113.点此复制
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