---
title: "NR2F1 controls a retinoic acid–CYP26A1 network that shapes retinal specialization and reveals fove"
id: "biorxiv-6-an-nr2f1-dependent-retinoic-acid-network-controls-retinal-specialization-in"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-6-an-nr2f1-dependent-retinoic-acid-network-controls-retinal-specialization-in"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.22.753406v1?rss=1"
published_at: "2026-09-23T09:50:14.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# NR2F1 controls a retinoic acid–CYP26A1 network that shapes retinal specialization and reveals fove
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-6-an-nr2f1-dependent-retinoic-acid-network-controls-retinal-specialization-in
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.22.753406v1?rss=1)
- **Published At:** 2026-09-23T09:50:14.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study identifies an **NR2F1-dependent** transcriptional program that is enriched for **retinoic acid (RA)** pathway genes and is required for normal retinal regionalization in mice. - Single-cell RNA sequencing across three complementary Nr2f1 mouse models, including two patient-specific mutations, defined a shared Nr2f1-driven gene expression signature. - Loss or mutation of Nr2f1 altered spatial RA signaling: the dorso-equatorial expression domain of **Cyp26a1** expanded into ventral retina while ventral determinants such as Vax2 were reduced. - These molecular changes correlated with shifts in the dorso-ventral distribution of S- and M-opsin–expressing cone photoreceptors, indicating disrupted retinal specialization. - Human NR2F1 was shown to bind a conserved regulatory region upstream of **CYP26A1**, supporting a direct regulatory role of NR2F1 on local RA catabolism. - High-resolution optical coherence tomography (OCT) in individuals with Bosch-Boonstra-Schaaf optic atrophy syndrome (**BBSOAS**, caused by NR2F1 variants) revealed consistent foveal abnormalities: a smaller, shallower foveal pit and increased central retinal thickness, interpreted as **foveal hypoplasia**. - The work links an NR2F1–RA/CYP26A1 regulatory axis to retinal regionalization and provides evidence for a retina-intrinsic contribution to the visual impairment seen in BBSOAS patients. - The article is a preprint and has not undergone peer review; methodological and detailed quantitative results were reported in the source but are not reproduced here beyond these summary findings.
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Schaaf, [ View ORCID Profile](http://orcid.org/0000-0002-1338-8476)Seth Blackshaw, [ View ORCID Profile](http://orcid.org/0000-0001-7847-9320)Patrick Yu-Wai-Man, [ View ORCID Profile](http://orcid.org/0000-0002-4402-4974)Michele Bertacchi, [ View ORCID Profile](http://orcid.org/0000-0001-7105-2957)Michele Studer doi: https://doi.org/10.64898/2026.09.22.753406 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. Paolo Piovani 1 Institute of Biology Valrose - University Cote d'Azur- Nice, France; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Paolo%2BPiovani%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Piovani%20P&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3APaolo%2BPiovani%2B) * [ORCID record for Paolo Piovani](http://orcid.org/0009-0004-7694-7687 "Open in new tab") Carole Belliardo 2 University Cote d'Azur - Nice, France; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Carole%2BBelliardo%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Belliardo%20C&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ACarole%2BBelliardo%2B) * [ORCID record for Carole Belliardo](http://orcid.org/0000-0002-8677-1783 "Open in new tab") Rahul Makam 3 Moorfields Eye Hospital NHS Foundation Trust, London, UK; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Rahul%2BMakam%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Makam%20R&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ARahul%2BMakam%2B) * [ORCID record for Rahul Makam](http://orcid.org/0000-0002-9077-8945 "Open in new tab") Boglarka Zambo 4 Institute of Biology Valrose - University Cote d'Azur - Nice, France; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Boglarka%2BZambo%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Zambo%20B&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ABoglarka%2BZambo%2B) Annabelle Mantilleri 4 Institute of Biology Valrose - University Cote d'Azur - Nice, France; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Annabelle%2BMantilleri%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Mantilleri%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAnnabelle%2BMantilleri%2B) * [ORCID record for Annabelle Mantilleri](http://orcid.org/0009-0006-5015-4122 "Open in new tab") Amandine Chassot 4 Institute of Biology Valrose - University Cote d'Azur - Nice, France; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Amandine%2BChassot%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Chassot%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAmandine%2BChassot%2B) * [ORCID record for Amandine Chassot](http://orcid.org/0000-0003-1242-9456 "Open in new tab") Gergo Gogl 4 Institute of Biology Valrose - University Cote d'Azur - Nice, France; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Gergo%2BGogl%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Gogl%20G&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AGergo%2BGogl%2B) * [ORCID record for Gergo Gogl](http://orcid.org/0000-0002-8597-3711 "Open in new tab") Christian P. Schaaf 5 Institute of Human Genetics, Heidelberg University, Heidelberg, Germany; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Christian%2BP.%2BSchaaf%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Schaaf%20CP&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AChristian%2BP.%2BSchaaf%2B) * [ORCID record for Christian P. 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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. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared Fondation pour la Recherche Médicale, https://ror.org/04w6kn183, EQU202003010222 Fondation de France, 00123416, 00154573 ATIP-Avenir Program CNRS Starting Grant 2025 France 2030 ANR-15-IDEX-01 Fondation Maladies Rares, Omics2024-1514
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