The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis
Abstract
Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GTPases, suggesting an important role for Rho signaling in cognitive function. It remains unknown, however, how mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a Rho-GTPase activating protein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis. Using RNA interference and antisense RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons in rat hippocampal slices significantly decreases spine length. This phenotype can be recapitulated using an activated form of RhoA and rescued by inhibiting Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by increasing RhoA and Rho-kinase activities. We further demonstrate an interaction between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings provide the first insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.
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Alterations in the regulation of actin at dendritic spines by neurodevelopmental disease-associated proteins such as DISC1, DTNBP1, SHANK3, PAK3, Oligophrenin and SRGAP2 produce deficits in synaptic plasticity and in the formation and consolidation of long-term memories.
“Moreover, alterations in the regulation of actin at dendritic spines, by neurodevelopmental disease-associated proteins such as DISC1, DTNBP1, SHANK3, PAK3, Oligophrenin and SRGAP2, have been shown to produce deficits in both synaptic plasticity and the formation and consolidation of long-term memories.23, 24, 25, 26, 27, 28, 29”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [27]
CYFIP1 is part of a growing number of mental illness-associated actin-regulatory molecules, including DISC1, DTNBP1, SHANK3, SRGAP2, Oligophrenin and the Abi1-WAVE2 complex, that act in Rac1-dependent pathways to regulate dendritic development and spine dynamics.
“Our results suggest that CYFIP1 is part of a growing number of mental illness-associated actin-regulatory molecules, including DISC1, DTNBP1, SHANK3, SRGAP2, Oligophrenin and the Abi1-WAVE2 complex that act in Rac1-dependent pathways to regulate dendritic development and spine dynamics.24, 25, 26, 27, 28, 29”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [27]
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References 52 · Cited by 293
- Authors
- Govek, E.-E., Newey, S. E., Akerman, C. J., Cross, J. R., Van der Veken, L., & Van Aelst, L.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Venue
- Nature Neuroscience
- Published
- 2004-03-14
- Volume
- 7
- Issue
- 4
- Pages
- 364-372
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1982121383
- Cited by
- 293
- References
- 52
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 9 · 2020: 11 · 2019: 2 · 2018: 9 · 2017: 14 · 2016: 15 · 2015: 15 · 2014: 21 · 2013: 22 · 2012: 22
- FWCI
- 10.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Dana Foundation
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- OPHN1, X-linked intellectual disability, dendritic spine morphogenesis, Rho GTPase signaling, RhoA, Rho kinase, Homer, CA1 hippocampal neurons, spine length, cognitive function
- MeSH terms
- Animals, Cytoskeletal Proteins, Dendrites, Hippocampus, Morphogenesis, Neurons, Nuclear Proteins, Organ Culture Techniques, Synapses, Transfection, Down-Regulation, RNA, Antisense, Neurites, GTPase-Activating Proteins, RNA Interference, X-Linked Intellectual Disability, Cell Size, Mice, Rats
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