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

EMBO Mol Med. 2019 Aug;11(8):e10291. doi: 10.15252/emmm.201910291. Epub 2019 Jul 18.

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 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.

Keywords: BBSOA syndrome; astrogliosis; mouse Nr2f1; myelination; optic nerve atrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / ultrastructure
  • Behavior, Animal
  • COUP Transcription Factor I / deficiency
  • COUP Transcription Factor I / genetics*
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Haploinsufficiency*
  • Heterozygote
  • Humans
  • Learning
  • Mice, Knockout
  • Miconazole / pharmacology
  • Nerve Fibers, Myelinated / drug effects
  • Nerve Fibers, Myelinated / metabolism
  • Nerve Fibers, Myelinated / ultrastructure*
  • Neural Conduction
  • Oligodendroglia / metabolism
  • Oligodendroglia / ultrastructure
  • Optic Atrophy, Autosomal Dominant / drug therapy
  • Optic Atrophy, Autosomal Dominant / genetics*
  • Optic Atrophy, Autosomal Dominant / metabolism
  • Optic Atrophy, Autosomal Dominant / pathology
  • Optic Nerve / drug effects
  • Optic Nerve / metabolism
  • Optic Nerve / ultrastructure*
  • Visual Perception

Substances

  • COUP Transcription Factor I
  • NR2F1 protein, human
  • Nr2f1 protein, mouse
  • Miconazole