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P. H. Frederikse, C. L. Bitel; REST/NSRF Regulation of Synaptic Vesicle Machinery Proteins and Neuronal miRNA Expression in Lens Demonstrates Fundamental Cell Identity Mechanisms Are Uniquely Shared in Neurons and Lens Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4348.
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© ARVO (1962-2015); The Authors (2016-present)
We demonstrate a fundamental role for the neuron master regulatory transcription factor REST/NSRF in lens similar to brain. These studies are designed to extend understanding of the striking degree of uniquely shared molecular regulatory mechanisms and cell biology that fundamentally define neuron cell identity and development, in lens. REST has a key role in stem cells, Alzheimer’s and Huntington’s disease, seizures, and a basic role in oxidative stress responses in neurons. These studies underscore a shared stress diathesis model in lens and brain, consistent with the shared fundamental disease mechanisms in these two organs.
Mouse and rat lenses were analyzed for REST and its isoforms, and neuronal gene expression by immunoprecipitation, immunoblot, northerns, and in situ protein localization. Gel shift assays were used to analyze NSRE binding at cognate sites.
The neuronal master regulatory transcription factor REST, and isoforms that governs ~1500 neuronal genes, are expressed in lens with a spatial distribution consistent with REST having a critical role in lens development similar to neurons, and determining expression of neuronal genes in lens (e.g. Synapsin, TUJ1, miR-124).
We have now identified three major tiers of fundamental determinants of neuronal cell identity that are uniquely shared with the lens: synaptic vesicle transport, micro RNA regulation, and the master regulatory REST transcription factor that is key to neuronal gene expression and cell differentiation. We expand on findings from our lab that identified a remarkable and extensive sharing of synaptic vesicle transport proteins, and neuronal motor proteins, tubulins and miRNAs in lens, and demonstrate the global regulatory transcription factor REST functions similarly in lens. Our data indicate a mechanism for REST splicing, and also RILP control of REST nuclear import, in lens development. Moreover, lens expression of synaptic vesicle transport machinery and neuronal miRNAs is conserved in invertebrates, and REST has an over-arching role in determining gene expression, stem cell biology and establishing cell identity in neurons. In light of observations that lens ontogeny and phylogeny preceded that of the brain, the data suggest an even more important role for the lens in the evolution of hallmark cell biology and molecular regulation that established neuronal cell identity, and as a result, indicate further that lens and brain share even more levels of basic disease mechanisms in response to stress and aging.
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