An NR2F1-dependent retinoic acid network controls retinal specialization in mice and reveals foveal hypoplasia in patients with BBSOAS
- 1Institute of Biology Valrose (iBV) - University Cote d'Azur - Nice, France
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.
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BibTeX
@misc{piovani2026nr2f1dependent,
title = {{An NR2F1-dependent retinoic acid network controls retinal specialization in mice and reveals foveal hypoplasia in patients with BBSOAS}},
author = {P. Piovani and C. Belliardo and R. Makam and B. Zambo and A. Mantilleri and A. Chassot and G. Gogl and C. P. Schaaf and S. Blackshaw and P. Yu-Wai-Man and M. Bertacchi and M. Studer},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753406},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753406v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - An NR2F1-dependent retinoic acid network controls retinal specialization in mice and reveals foveal hypoplasia in patients with BBSOAS
AU - P. Piovani
AU - C. Belliardo
AU - R. Makam
AU - B. Zambo
AU - A. Mantilleri
AU - A. Chassot
AU - G. Gogl
AU - C. P. Schaaf
AU - S. Blackshaw
AU - P. Yu-Wai-Man
AU - M. Bertacchi
AU - M. Studer
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753406
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753406v1
AB - 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.
ER -