Genetic analysis of SOX2 function in mouse neural progenitors Public Deposited

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  • March 21, 2019
  • Taranova, Olena V.
    • Affiliation: School of Medicine, UNC Neuroscience Center, Neuroscience Curriculum
  • Cells of the nervous tissue that preserve the capacity to divide and differentiate in neurons and glia are defined as neural progenitor cells (NPCs). Within central nervous system (CNS) the NPCs express SOX2, a protein of SoxB1 subgroup of HMG-box superfamily of transcription factors. To address function of SOX2 in vivo we used gene targeting in embryonic stem cells to engineer a conditional null (Sox2cond) and two hypomorphic (Sox2IR and Sox2lP) alleles of the mouse gene. Sox2cond allows removal of the SOX2 coding sequence using CRE recombinase while Sox2IR and Sox2lP alleles sustain gene expression at 20-40% and 15-30%, respectively, of the level in wild-type mice. To address the development of NPCs in vivo we focused on mouse retina, an essential part of the vision system. As an isolated and well-defined structure of CNS, retina became a well-characterized model for studies of molecular mechanisms of neurogenesis. Conditional ablation of Sox2 in the mouse retina results in the complete loss of neural progenitor competence, so that Sox2-null cells do not contribute to the dividing progenitor population and do not differentiate into neurons or glia. Lowering the levels of Sox2 expression below 50%, achieved in compound hypomorphic-null animals restricts the capacity of retinal NPCs, resulting in aberrant neuronal differentiation evident from disruption of retinal nuclear laminas and malformed neuritic connections. Our findings demonstrate furthermore that SOX2 activity has wide effect on gene expression. In particular it is required for expression of proneural genes and, in a concentration dependent manner, Notch pathway genes in retinal progenitors. Collectively, these studies reveal an essential dosage-sensitive regulation of neural progenitor competence by SOX2. We show here that SOX2 is uniquely required for mouse retina development. SOX2 is mutated in about 10% of anophthalmia or severe microphthalmia cases in humans (Fantes, Ragge et al. 2003). The current study demonstrates a similar phenotype in Sox2 mutant mice, hence, supplying a mouse model for the analysis of developmental defects in SOX2 anophthalmia syndrome.
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  • Pevny, Larysa
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