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D. Sinha, A. Klise, S. L. Hose, C. Zhang, B. K. Padhi, J. S. Zigler, Jr.; Excess Winged Helix Transcription Factor Foxg1 in Nuc1 Astrocytes is a Possible Cause for the Retinal Remodeling Abnormality in the Nuc1 Spontaneous Mutant Rat. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3723.
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In the neural retina, βA3/A1-crystallin is expressed only in astrocytes. The Nuc1 phenotype results from mutation of the βA3/A1-crystallin gene. The purpose of this study is to better understand the molecular mechanisms by which the mutation affects the remodeling of the retina.
During development,apoptosis is associated with remodeling of the retina. TUNEL staining, retinal morphometry and immunofluorescence studies using specific neuronal, astrocyte and blood vessel markers were used to analyze this process. Microarray analysis was performed using the Affymetrix system; Ingenuity pathway analysis software identified functional groups of genes differentially regulated in Nuc1 astrocytes. In addition, Real-time PCR analysis was used to determine the expression of certain transcription factors downstream of selected signaling pathways.
Excess neurons and endothelial cells remain in the Nuc1retina during development, suggesting a deficiency in the apoptotic process normally associated with remodeling. Based on microarray analysis, different functional groups of genes were combined into networks. Major network changes observed included the neurogenesis genes NrCam, PtprZ1, Ascl1, Olig1, Aspa, Apoe, Ntrk2, Mt3 and Fez1 (Upregulated in Nuc1) and vessel development genes such as Cyr61, Serpine 1, Cspg4, tgfα, figf (downregulated in Nuc1) and Apln, Ednrb, Sult1a1 and Cxcr4 (upregulated in Nuc1). Real-time RT-PCR confirmed marked upregulation of FoxG1 in Nuc1 astrocytes.
Our studies suggest that the mutant protein affects several pathways in the signaling web, such as the insulin and PI-3 kinase pathways. However, it is tempting to speculate that the failure of the Nuc1 retina to remodel could be an effect of FoxG1 as it has been shown earlier that FoxG1 plays an important role in the regulation of neuronal cell apoptosis.
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