Graded Otx2 activities demonstrate dose-sensitive eye and retina phenotypes
Open accessAbstract
In the human, mutations of OTX2 (Orthodenticle homeobox 2 transcription factor) translate into eye malformations of variable expressivity (even between the two eyes of the same individual) and incomplete penetrance, suggesting the existence of subtle thresholds in OTX2 activity. We have addressed this issue by analyzing retinal structure and function in six mutant mice with graded Otx2 activity: Otx2+/+, Otx2+/AA, Otx2+/GFP, Otx2AA/AA, Otx2AA/GFP and Otx2GFP/GFP. Null mice (Otx2GFP/GFP) fail to develop the head and are embryonic lethal, and compound heterozygous Otx2AA/GFP mice show a truncated head and die at birth. All other genotypes develop until adulthood. We analyzed eye structure and visual physiology in the genotypes that develop until adulthood and report that phenotype severity parallels Otx2 activity. Otx2+/AA are only mildly affected whereas Otx2+/GFP are more affected than Otx2+/AA but less than Otx2AA/AA mice. Otx2AA/AA mice later manifest the most severe defects, with variable expressivity. Electrophysiological and histological analyses of the mouse retina revealed progressive death of bipolar cells and cone photoreceptors that is both Otx2 activity- and age-dependent with the same ranking of phenotypic severity. This study demonstrates the importance of gene dosage in the development of age-dependent pathologies and underscores the fact that small gene dosage differences can cause significant pathological states.
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PNNs have been proposed as indispensable mediators of the modulation of synaptic plasticity by the transcription factor Otx2.
“Interestingly, PNNs have been proposed as indispensable mediators of the modulation of synaptic plasticity by the transcription factor Otx259–61.”
From Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses (2019) · cites this paper as [61]
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- Authors
- Bernard, C., Kim, H.-T., Torero Ibad, R., Lee, E. J., Simonutti, M., Picaud, S., Acampora, D., Simeone, A., Di Nardo, A. A., Prochiantz, A., Moya, K. L., & Kim, J. W.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Korea Advanced Institute of Science and Technology (KR)
- 1 Collège de France, Center for Interdisciplinary Research in Biology, UMR CNRS 7241/INSERM U1050, 11 place Marcelin Berthelot, Paris 75005, France
- Istituto Neurologico Mediterraneo (IT)
- Corresponding author
- Moya, Kenneth L.
- Kim, Jin Woo
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-11-13
- Volume
- 23
- Issue
- 7
- Pages
- 1742-1753
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2170561922
- Cited by
- 39
- References
- 29
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 7 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 4 · 2015: 6 · 2014: 3
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (other-oa)
- Funders
- Agence Nationale de la Recherche (ANR-11-BSV4-0024)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Ocular Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Otx2, gene dosage, compound heterozygosity, ocular malformations, retinal degeneration, variable expressivity, incomplete penetrance, retinal development, visual physiology, mouse model
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Eye Abnormalities, Mice, Inbred C57BL, Mice, Transgenic, Visual Acuity, Retinal Cone Photoreceptor Cells, Gene Expression Regulation, Developmental, Gene Dosage, Penetrance, Green Fluorescent Proteins, Retinal Bipolar Cells, Retinal Horizontal Cells, Mice, Otx Transcription Factors
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