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Intrinsic Mechanisms Governing Retinal Progenitor Cell Biology: Retinal Homeobox Transcriptional Regulation and the Function of Forkhead Transcription Factors During Eye Development

Moose, Holly Elizabeth
http://rave.ohiolink.edu/etdc/view?acc_num=osu1251827616

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Integrated Biomedical Sciences.
Understanding the development and maintenance of Retinal Progenitor Cells (RPCs) is critical to understanding normal and disease processes within the neural retina. To understand RPC biology, it is important to understand the transcriptional regulation of known intrinsic regulators, and continue to identify new RPC expressed genes to demonstrate their function during eye development. The studies presented in this work address the transcriptional regulation of the Xenopus laevis Rx gene product, Rx2A, and function of two newly recognized RPC genes, FoxO3 and FoxM1.We characterized a region of genomic sequence upstream of the Rx2A coding region using GFP transgenes in X. laevis embryos. We have identified several cis-acting elements that work cooperatively to regulate gene expression, including a element conserved in the human Rx homologue and a novel forkhead binding element (FBE). We also demonstrate transcription factor sites for POU, OTX and SOX proteins within the Rx promoter ensure temporal and spatial specificity to gene expression. This work furthers our understanding of how this primary retinal transcription factor is regulated. This is applicable to the understanding of RPC development since Rx is one of the eye specific transcription factors expressed during RPC specification. We pursued studies of FoxO3 and FoxM1 in the developing neural retina to further the understanding of RPC regulation by forkhead transcription factors. These two factors were chosen for co-current studies for the following reasons: (1) neither gene product had been ascribed a role in developing RPCs, (2) their known functions suggested they act in opposing ways with regards to the cell cycle, and (3) due to their expression patterns both FoxO3 and FoxM1 serve as candidate factors to regulate the Rx2A promoter through the FBE. To define the role of FoxO3 during vertebrate eye development, we overexpressed FoxO3 RNA in the anterior neural plate of X. leavis embryos. FoxO3 overexpression results in embryos with small eyes. The small eye phenotype is a result of decreased proliferation, induction of apoptosis, and changes in RPC gene expression. The changes in gene expression suggest that FoxO3 can function to delay the differentiation of RPCs, although they are properly specified. The data supports our original hypothesis regarding FoxO3 as cell cycle antagonist with the ability to alter the differentiation capacity of RPCs. To investigate the function of FoxM1 in developing RPCs, we performed loss-of-function studies using morpholino oligonucleotides (MO). FoxM1 knockdown in the anterior neural region of X. laevis results in a dose-dependant small eye phenotype and clear defects in retinal lamination. Our data reveals that FoxM1 is not necessary for the specification of RPCs, and suggests that differentiation into the Muller glia, and rod photoreceptor lineages is possible with reduced levels of FoxM1. The studies presented concern the transcriptional regulation of the Rx gene product, Rx2A, and a role of FoxO3 and FoxM1 during RPC development. Collectively, they represent an advancement in the knowledge regarding two important intrinsic mechanisms governing RPC development: transcriptional regulation and transcription factor function.
Heithem El-Hodiri (Advisor)
Christine Beattie (Committee Member)
Andy Fischer (Committee Member)
John Oberdick (Committee Member)
183 p.
Biology; Biomedical Research
forkhead; homeobox; retinal progenitors; transcription; cell cycle

Recommended Citations

Citations

  • Moose, H. E. (2009). Intrinsic Mechanisms Governing Retinal Progenitor Cell Biology: Retinal Homeobox Transcriptional Regulation and the Function of Forkhead Transcription Factors During Eye Development [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1251827616

    APA Style (7th edition)

  • Moose, Holly. Intrinsic Mechanisms Governing Retinal Progenitor Cell Biology: Retinal Homeobox Transcriptional Regulation and the Function of Forkhead Transcription Factors During Eye Development. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1251827616.

    MLA Style (8th edition)

  • Moose, Holly. "Intrinsic Mechanisms Governing Retinal Progenitor Cell Biology: Retinal Homeobox Transcriptional Regulation and the Function of Forkhead Transcription Factors During Eye Development." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1251827616

    Chicago Manual of Style (17th edition)

osu1251827616
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© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.