Defininig the Relationship Between the Homeobox Gene VSX2 and Extrinsic Signaling in the Regulation of Retinal Progenitor Cell Properties

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Publication Type dissertation
School or College School of Medicine
Department Neurology
Author Sigulinsky, Crystal Lynn
Title Defininig the Relationship Between the Homeobox Gene VSX2 and Extrinsic Signaling in the Regulation of Retinal Progenitor Cell Properties
Date 2012-12
Description Development of the neural retina is a complex process requiring step-wise induction of specified retinal progenitor cells (RPCs) from the neural ectoderm and their coordinated proliferative expansion and differentiation into the mature neurons and glia of the adult retina. The homeobox gene Vsx2 is expressed in RPCs and required for proper execution of this retinal program. In the absence of Vsx2 function, maintenance of retinal identity, RPC proliferation, and retinal neurogenesis are disrupted, with serious consequences on overall ocular development and visual function. Despite the obvious importance of Vsx2, an understanding of the molecular mechanisms by which Vsx2 regulates these processes is lacking and few direct targets have been identified. To further define the role of Vsx2, we sought to determine the relationship between Vsx2 and the extrinsic signaling pathways regulating RPC properties. Through the analysis of genetic chimeras and candidate signaling pathways, we evaluated the contribution of Vsx2 to the regulation of extrinsic signaling pathways involved in the cellular processes of retinal development. We find that Vsx2 mediates the response of RPCs to the signals driving retinal specification and maintenance, largely through cell autonomous repression of the RPE determinant Mitf. We also find that Vsx2-deficient RPCs exhibit a robust cell autonomous delay in the initiation of retinal neurogenesis, revealing an essential role for Vsx2 in the temporal regulation of neurogenic competence. In contrast, we find that regulation of RPC proliferation by Vsx2 involves significant cell nonautonomous iv contributions, suggesting an important role for Vsx2 in regulating the availability of retinal proliferation signals. Analysis of the retinal mitogen Sonic Hedgehog (Shh) and its signaling pathway in Vsx2-deficient retinas further supported this role, demonstrating that Vsx2 is required to ensure sufficient availability of Shh. We also describe a potential role for Vsx2 in the regulation of RPC responsiveness to Hedgehog (Hh) pathway stimulation. Taken together, the data presented in this dissertation demonstrate the requirement for Vsx2 in promoting both the reception and availability of the extrinsic signals necessary for the regulation of RPC properties, thereby ensuring the proper growth and differentiation of this important sensory tissue.
Type Text
Publisher University of Utah
Subject MESH Retina; Stem Cells; Neurons; Genes, Homeobox; Transcription Factors; Visual Pathways; Retinal Ganglion Cells; Amacrine Cells; Retinal Bipolar Cells; Retinal Horizontal Cells; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Gene Expression; Cell Differentiation; Photoreceptor Cells; Pigment Epithelium of Eye; Homeodomain Proteins; Hedgehog Proteins; Morphogenesis; Retinal Development
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital reproduction of Defining the Relationship Between the Homeobox Gene VSX2 and Extrinsic Signaling in the Regulation of Retinal Progenitor Cell Properties. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriot Library Special Collections.
Rights Management Copyright © Crystal Lynn Sigulinsky 2012
Format Medium application/pdf
Format Extent 15,531,919 bytes
Source Original in Marriott Library Special Collections, QH9.7 2012.S53
ARK ark:/87278/s65b39nw
Setname ir_etd
Date Created 2014-05-02
Date Modified 2021-05-06
ID 196397
Reference URL https://collections.lib.utah.edu/ark:/87278/s65b39nw
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