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Peter H. Frederikse, Claudine L. Bitel; Fundamental Genetic Switch Components That Determine Neuronal Cell Identity Are Also and Uniquely Used In The Lens. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2768.
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© ARVO (1962-2015); The Authors (2016-present)
Recent work from our laboratory showed that fundamental factors which make up a series of genetic switches that govern neurogenesis are also used in the lens. Analogous to what occurs during neurogenesis the REST/NRSF "master neuronal transcription factor", ubiquitous HuR and PTB and are expressed in lens epithelial cells. However, similar to neurogeneis these factors are replaced by alternatively spliced REST4, neuronal HuB/C/D, nPTB and "brain specific" Fox-1 and Fox-2 isoforms in post-mitotic elongating lens fiber cells. In addition, miR-124 which is also integrated into this network is expressed in lenses. In neurons, nPTB, HuB/C/D and neural Fox-1,2 isoforms mediate a comprehensive reprogramming of alternative splicing that defines neurons. Here we examine how these factors are integrated during lens differentiation vs. their roles in neurogenesis.
Immunoblots, RT-PCR, IHC, IF and Immunoprecipitation were used to identify molecular genetic switch components in the lens, and to identify and characterize neuronal gene products and neuronal alternatively spliced transcripts in lenses.
REST4, nPTB, HuB/C/D and neuronal isoforms of Fox-1 are expressed in lens fiber cells, and also serve to confine their own expression to post-mitotic lens fiber cells and neuronal cells. nPTB alternative splicing is regulated by miR-124 and Fox-1 which both also occur in lenses, consistent with nPTB protein in post-mitotic fiber cells. In addition we showed alternative transcripts in lenses previously classified as neuron-specific.
Our results extend and integrate findings from our previous studies showing neural gene expression and neuronal alternative splicing in lens fiber cells, and the mutually expression of key factors that make up a fundamental regulatory network which governs neurogenesis and neuronal cell identity in lens epithelial vs. fiber cells. These findings expand this unique conceptual framework for understanding extensive similarities between lens and neuronal cell morphology, molecular regulation, physiology, and development. Understanding the role of neural and non-neural REST/NRSF, PTB, Hu and Fox-1 isoforms in the lens, and roles of miR-124, miR-125 and let-7 that are also integrated in this regulatory network, can help us to more fully understand lens biology and evolution. Finally, these findings also provide a further basis fort understanding shared disease phenotypes and responses to systemic pathophysiology and metabolic disease in lens and brain.
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