Mouse Nr2f1 haploinsufficiency unveils new pathological mechanisms of a human optic atrophy syndrome

Optic nerve atrophy represents the most common form of hereditary optic neuropathies leading to vision impairment. The recently described Bosch‐Boonstra‐Schaaf optic atrophy (BBSOA) syndrome denotes an autosomal dominant genetic form of neuropathy caused by mutations or deletions in the NR2F1 gene. Herein, we describe a mouse model recapitulating key features of BBSOA patients—optic nerve atrophy, optic disc anomalies, and visual deficits—thus representing the only available mouse model for this syndrome. Notably, Nr2f1 ‐deficient optic nerves develop an imbalance between oligodendrocytes and astrocytes leading to postnatal hypomyelination and astrogliosis. Adult heterozygous mice display a slower optic axonal conduction velocity from the retina to high‐order visual centers together with associative visual learning deficits. Importantly, some of these clinical features, such the optic nerve hypomyelination, could be rescued by chemical drug treatment in early postnatal life. Overall, our data shed new insights into the cellular mechanisms of optic nerve atrophy in BBSOA patients and open a promising avenue for future therapeutic approaches. Synopsis This study proposes Nr2f1 heterozygous mice as a model of BBSOA syndrome, an optic nerve (ON) atrophy associated with intellectual disability. Nr2f1 mutants reveal ON hypomyelination, astrogliosis and reduced axonal conductance velocity. Treatment with Miconazole rescues ON myelination defects. Mouse Nr2f1 and human NR2F1 expression profiles are highly conserved in the developing retina and ON. Nr2f1 heterozygous and homozygous mutant mice recapitulate the human disease, displaying optic disc abnormalities, cerebral visual impairment and ON atrophy. Nr2f1 regulates retinal ganglion cell differentiation and accurate balance between ON oligodendrocytes and astrocytes. Nr2f1 modulates ON axonal conductance velocity and is involved in associative visual learning. Miconazole treatment at early postnatal ages rescues ON myelination level, hence representing a promising therapeutic approach for optic neuropathies. Graphical Abstract This study proposes Nr2f1 heterozygous mice as a model of BBSOA syndrome, an optic nerve (ON) atrophy associated with intellectual disability. Nr2f1 mutants reveal ON hypomyelination, astrogliosis and reduced axonal conductance velocity. Treatment with Miconazole rescues ON myelination defects.