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M.C. Madhavan, J.R. Spence, A.M. Rorick, K. Del Rio–Tsonis; MAP Kinases Induce Transdifferentiation During Chick Retina Regeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5349.
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Purpose: The embryonic chick has the ability to regenerate its retina. This regeneration occurs only in the presence of an exogenous source of FGF–2 and only during a small window of development. We have shown previously that retina regenerates through transdifferentiation of the Retinal Pigment Epithelium (RPE) and also from stem/progenitor cells in the anterior portion of the eye. During the process of transdifferentiation, the RPE looses its characteristic pigmented phenotype, proliferates to form a multilayered neuroepithelium and then differentiates into the various retinal cell types. This current study aims to dissect the cascade of cellular events that enable the RPE in the embryonic chick to transdifferentiate into retina in response to an FGF–2 signal. Methods: We use Immunohistochemistry to show the activation of the MAP Kinase pathway in regeneration. We also use immunohistochemistry to show that during transdifferentiation, RPE cells downregulate the RPE specific transcription factor, Microphthalmia (Mitf). To show functional relevance of the immunohistochemical data, we over–express a constitutively active form of MEK, using an RCAS virus. We also overexpress Mitf and assess if overexpression of Mitf prevents FGF–2 induced transdifferentiaion. The data from these over–expression experiments are analyzed using histology and Immunohistochemistry Results: Immunohistochemical analysis show that ERK is activated in the RPE and Mitf is downregulated in the RPE during transdifferentiation. We further show that transdifferentiation of the RPE is caused in response to activation of MEK in the absence of FGF–2. Also transdifferentiation is inhibited when Mitf is overexpressed in the RPE even in the presence of an FGF–2 signal. Conclusions: Our results indicate that during regeneration MEK and ERK are activated and Mitf is downregulated in the RPE.
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