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

Michele Bertacchi,Paola Bovolenta,Paolo Giacobini,Agnès Gruart,Polynikis Kaimakis,José M Delgado‐García,Michèle Studer,Linda Serra,Cécile Allet

doi:10.15252/emmm.201910291

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.

Highlights

The dorsal region of the mammalian telencephalon generates the neocortex and the related cingulate/retrosplenial cortex and hippocampus
Once specified along the dorso-ventral axis, mostly by the interplay of Shh and Fgf signaling pathways, the dorsal telencephalon is soon subdivided in different regions: cells at the midline are patterned as the choroid plaque, the future choroid plexus, followed, in a medial to lateral order, by a group of cells known as the cortical hem, the hippocampal primordium and the prospective isocortex (Hebert and Fishell 2008; Hoch et al 2009; Abellan et al 2014)
Control and coordination of signaling pathways is fundamental for tissue specification and organ development. Consistent with this idea, we have demonstrated that the secreted protein Secreted Frizzled Related Protein 1 (Sfrp1), known to modulate Bmp, Wnt and Notch signaling in different contexts, is required to subdivide and shape the dorsal telencephalon with a dual role

Summary

Introduction

The dorsal region of the mammalian telencephalon generates the neocortex and the related cingulate/retrosplenial cortex and hippocampus. These structures are the final result of the highly regulated genetic network underlying telencephalic development and are collectively responsible for “higher-order” functions, including for example language or memory. Once specified along the dorso-ventral axis, mostly by the interplay of Shh and Fgf signaling pathways, the dorsal telencephalon is soon subdivided in different regions: cells at the midline are patterned as the choroid plaque, the future choroid plexus, followed, in a medial to lateral order, by a group of cells known as the cortical hem, the hippocampal primordium and the prospective isocortex (Hebert and Fishell 2008; Hoch et al 2009; Abellan et al 2014). Specification of the choroid plaque and cortical hem depends on the activity of BMPs, which are expressed by the dorsal telencephalic midline itself. Ectopic expression of a constitutively active form of βcatenin induces cortical cells to adopt a hippocampal fate (Machon et al 2007)

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