A comparative analysis of Otd/OTX function in the Drosophila eye: examining mechanisms of evolutionarily conserved function

• Main Author: Terrell, David A
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2013
• Subjects: Developmental biology; Molecular biology
• ISBN: 9781303747489; 1303747480

Otd-related transcription factors are evolutionarily conserved to control anterior patterning and neurogenesis. Mutations in two human Otd-related gene products, OTX2 and CRX, associate with several photoreceptor-specific retinopathies and both factors are expressed in all photoreceptors from early specification through adulthood. However, it is not well understood how these factors function independently vs. redundantly, or how specific mutations in these factors lead to different disease outcomes. Drosophila encode a single Otd factor that has multiple functions during photoreceptor differentiation. In this work, we first define the functional domains of the Otd protein via a structure-function analysis. We then test the ability of human OTX1, OTX2, and CRX, as well as several disease-associated CRX alleles, to rescue the different functions of Otd. Our results indicate that: a) OTX2 and CRX rescue overlapping, yet distinct sub-functions of Otd during photoreceptor differentiation; b) CRX alleles can be functionally distinguished based on their rescue properties; and c) all three human Otd-related factors can rescue rhabdomeric photoreceptor morphogenesis. Together, the conserved functions of the Otd/OTX proteins suggest that the vertebrate OTX factors can interact with at least some of the same regulatory complexes as Otd in the Drosophila eye. Towards this end, I began to characterize the function of multiple Otd interaction partners in the Drosophila eye. We find that Otd genetically and physically interacts with a histone methyltransfesrase, G9a, and that this interaction is required to properly regulate the expression of specific Otd target genes (e.g. Rh5 expression). Overall, this work establishes the Drosophila eye as a unique model system to further study conserved functions of the OTX factors during photoreceptor development and differentiation.