An NR2F1-dependent retinoic acid network controls retinal specialization in mice and reveals foveal hypoplasia in patients with BBSOAS
Year: 2026
Type: preprint
Abstract: ABSTRACT The molecular programs that establish specialized retinal regions during development are essential for high-acuity vision, yet how their disruption contributes to human visual disorders remains poorly understood. Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), caused by pathogenic variants in NR2F1 and characterized by visual impairment, provides an opportunity to investigate these mechanisms. Using single-cell RNA sequencing of three complementary Nr2f1 mouse models, including two carrying patient-specific mutations, we identified a shared Nr2f1 -dependent transcriptional program enriched in retinoic acid (RA) pathway genes. Loss or mutation of Nr2f1 disrupted the spatial organization of RA signaling, most prominently by expanding the dorso-equatorial Cyp26a1 expression domain into ventral retina and reducing ventral determinants such as Vax2 . These molecular changes were associated with altered dorso-ventral distribution of S-and M-opsin-expressing cone photoreceptors. We further demonstrate that human NR2F1 binds a conserved regulatory region upstream of CYP26A1 , supporting its direct role in regulating local RA availability. Finally, high-resolution optical coherence tomography in individuals with BBSOAS revealed reproducible foveal abnormalities, including a smaller and shallower foveal pit and increased central retinal thickness, consistent with foveal hypoplasia. These findings uncover a previously unrecognized retina-intrinsic component of BBSOAS visual pathology and establish an NR2F1-RA/CYP26A1 regulatory axis linking developmental retinal regionalization to human foveal specialization.
Institutions: Centre National de la Recherche Scientifique, Inserm, Université Côte d'Azur, Institut de Biologie Valrose, Moorfields Eye Hospital NHS Foundation Trust, University of Cambridge, University College London, Heidelberg University, Johns Hopkins University, Johns Hopkins Medicine, University of California San Diego, Cambridge University Hospitals NHS Foundation Trust
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1415025379, G268257376, Evaluating Patient Outcomes and Therapies for Inherited Optic Neuropathies, G3527965702, G5549861300, G591700080, G659340285, G6731620517, Deconstructing gene regulatory networks for improving sight and brain disabilities, G8800819381, G880779785, Identification of gene regulatory networks controlling temporal patterning in retinal progenitor cells and neurogenic Müller glia
OpenAlex ID: W7214120875