Mitochondria are essential organelles that are dynamically regulated in neural cells. Although it is becoming clear that mitochondria regulation is key to control neurogenesis, the mechanisms governing mitochondrial dynamics in neural stem/progenitor cells (NSPCs) and neurons and its implication on neuronal maturation and plasticity remain largely elusive. We previously showed that the transcriptional regulator Nr2f1 is expressed in NSPCs and neurons of the mouse hippocampus and plays a crucial role in adult hippocampal neurogenesis. By studying its direct target genes, we recently found that Nr2f1 regulates a number of genes involved in mitochondrial dynamics and function. Accordingly, we observed a reduced mitochondrial mass and an increase of mitochondrial fragmentation in Nr2f1-deficient hippocampal neurons. These results are particularly relevant considering that mutations in NR2F1 coding sequence cause Boonstra-Bosch-Schaff optic atrophy syndrome (BBSOAS), a rare human autosomal-dominant neurodevelopmental disorder. BBSOAS is characterized by multiple clinical features, including optic nerve atrophy, intellectual disability and autistic traits which are compatible with altered mitochondrial function in the brain. Thus, Nr2f1-mediated control of mitochondrial dynamics in neural cells may contribute to the pathogenesis of BBSOAS. However, the effects of Nrf21-deficiency on mitochondrial dynamics and mitochondrial metabolism, and the consequences of these effects on the functional properties of Nr2f1-deficient NSPCs and neurons, are still unknown.
In this proposal, we plan to:
1) assess the transcriptional and biological pathways regulated by Nr2f1 through genome-wide molecular profiling of Nr2f1-deficient NSPC and neuronal cultures;
2) characterize the role of Nr2f1 on mitochondrial function unraveling its implications on maturation and plasticity of adult-born hippocampal neurons in the mouse;
3) develop new Medaka models for the study and treatment of BBSOAS.
To achieve these goals, the project gains on the complementarity of the four groups involved, with specific expertise in neurogenesis and functional characterization of neurons in mice models (U1, Turin), in the analysis of mitochondrial function in the CNS and in the development of vertebrate non-mammalian genetic model organisms for in vivo live imaging of neurons (U2, Naples), in the use of in vitro paradigms and transcriptomic/epigenomic approaches to dissect the molecular mechanisms underlying NSPC regulation (U3 and U4, Rome). By addressing the role of the Nr2f1-dependent mitochondrial alterations on the physiopathology of newborn hippocampal neurons and NSPCs, and their molecular underpinnings, this proposal shall lead to the identification of novel biomarkers and therapeutic targets for BBSOAS and other neurodevelopmental disorders associated with mitochondrial dysfunctions, paving the way towards the development of effective therapies.