Investigating temporal function of SOX2 transcription factor in retinal neural progenitor cells

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  • March 21, 2019
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  • Surzenko, Natalia
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
Abstract
  • Generation of the appropriate types and numbers of neurons and glia in the developing central nervous system (CNS) relies on complex networks of cell-intrinsic and cell-extrinsic factors regulating the proliferative and differentiating competence of neural progenitor cells. SOX2 transcription factor plays an essential role in specification and maintenance of multipotent neural progenitors, thus functioning as a molecular determinant of neural progenitor cell fate. Precise cellular and molecular mechanisms regulated by SOX2, however, remain poorly understood. In this study, using a series of Sox2 mutations in the mouse, we analyze cellular and molecular changes occurring downstream of SOX2 in two temporally defined sets of retinal neural progenitor cells. First, we describe experimental approaches aimed at characterization of global changes in gene expression in embryonic retinal neural progenitor cells of Sox2 mutants exhibiting severe developmental eye malformations, anophthalmia and microphthalmia. Specifically, through analysis of gene expression profiles in eye tissues of Sox2 wild type, heterozygous and compound null hypomorphic embryos, expressing progressively reduced levels of Sox2, we generated a database of genes transcriptionally misregulated as a consequence of reduction in Sox2 dosage. This analysis provides a basis for future investigation of cellular and molecular pathways regulated by SOX2 during eye development. Second, to examine cellular and molecular consequences of acute ablation of Sox2 in neural progenitor cells, we established methods for retina-specific temporally-regulated genetic ablation of Sox2 and for visualization of retinal progenitor cell behaviorin situ. Using these methods, we ablated Sox2 in the postnatal retina, and identified cell cycle progression as one of the cellular mechanism regulated by SOX2 in retinal Muller glia - the quiescent retinal progenitor cells. Furthermore, we established NOTCH1 signaling pathway as a downstream mediator of SOX2 function in retinal Muller glial cells. Combined together, our results provide new genetic evidence for cellular and molecular pathways regulated by SOX2 in retinal neural progenitors.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Neurobiology."
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  • Pevny, Larysa
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  • Chapel Hill, NC
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  • Open access

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