Transcriptional repression and activation are both necessary for the precise expression of the genes involved in the proper development of an organism. Aberrations in transcription factors that lead to dysfunctional proteins result in disease. Understanding the mechanisms in which transcription is regulated is vital to the identification of the factors and genetic networks that contribute to normal development. This information also provides a better understanding of the role mutations play in causing disruption in transcription factor function that leads to the impairment of developmental processes.
Homeobox genes are important for normal development. Arx is a member of the paired-type Aristaless-related family of homeobox proteins. Human mutations in Arx are associated with X-linked mental retardation and other neurological disorders. Findings from the studies of Arx deficient mice indicate the importance of Arx on brain development and neural cell migration. Therefore, Arx has emerged as a gene that is essential for normal brain development and is of major clinical significance. Despite what is known about Arx clinically, less is known about its molecular functions as a transcription factor and its downstream targets. It has been shown that Arx functions as a transcriptional repressor, but it is not clear how disease-associated mutations affect its function as a repressor.
This dissertation describes the consequence of two disease-associated mutations on the function of Arx as a transcriptional repressor. Two independent repression domains: the octapeptide and a novel domain located in the C-terminus were identified in Arx as well as the co-factors that mediate the repression through these domains. This work also describes the DNA binding ability of Arx. Additionally, the transcriptional function of another Aristaless-related homeobox protein, Retinal Homeobox (Rx) is also reported. Rx has been shown to be an activator of transcription, however this work found that the Rx has the ability to mediate repression. Together, the goal of this dissertation is to provide insight into the transcriptional functions of two related but functionally different paired-type Aristaless-related homeobox proteins: Arx and Rx. Furthermore, this work provides evidence for the function of the octapeptide motif in the context of a transcriptional repressor and an activator.