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

Abstract

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 NR 2F1 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.

Clinical and neurocognitive issues associated with Bosch‐Boonstra‐Schaaf optic atrophy syndrome: A case study

“…Deficits in nonverbal processing also may result from the patient's optic nerve hypoplasia (Bertacchi, Parisot, & Studer, ), though he did not show visual impairment, as seen in other reported BBSOAS cases (Chen et al, ). These findings are consistent with a study of heterozygous Nr2f1 deficient mice that show deficits in learning and processing visual information despite relatively unaffected visual acuity and general cognitive function (Bertacchi et al, ). Nr2f1 haploinsufficiency in mice led to defective optic nerve myelination and increased astrogliosis, resulting in slower optic axonal conduction velocity from the retina to higher level visual processing regions (Bertacchi, Gruart, et al, ).…”

“…These findings are consistent with a study of heterozygous Nr2f1 deficient mice that show deficits in learning and processing visual information despite relatively unaffected visual acuity and general cognitive function . Nr2f1 haploinsufficiency in mice led to defective optic nerve myelination and increased astrogliosis, resulting in slower optic axonal conduction velocity from the retina to higher level visual processing regions (Bertacchi, Gruart, et al, 2019). Thus, the patient's unique profile of impaired nonverbal abilities and minimal visual impairment suggests that his nonverbal deficits may reflect both the optic nerve hypoplasia and cerebral visual deficits, including alterations in thalamocortical development, abnormal optic nerve axonal conduction, and impaired visual learning and memory.…”

An Atlas of Cortical Arealization Identifies Dynamic Molecular Signatures

“…We detected TFs with established roles in arealization, such as NR2F1, which confers positional identity across the rostro-caudal axis 19 , and BCL11A, which interacts with NR2F1 and was recently shown to repress motor identity in the cortex 26 . Both genes are also implicated in neurodevelopmental disease 27,28 . We also detected TFs that, to our knowledge, have not been previously described in the context of cortical arealization.…”

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

“…It is worth to mention that alternative mechanisms of action may contribute to a direct increase of OL differentiation. Indeed, miconazole and ketoconazole appear to activate protein kinases [53,[56][57][58]. In particular, miconazole induces a strong phosphorylation of ERK1/2, whose constitutive activation has been correlated with a profound increase in the extent of remyelination after toxin-induced demyelinating injury [53,59].…”