Members of the Six4/5 family of homeobox transcription factors have been implicated in multiple human disorders, including type I mytonic dystrophy, branchio-oto-renal syndrome, and holoprosencephaly, suggesting a role for these factors in the nervous system development. Using a forward genetics approach, we identified unc-39, a C. elegans homologue of the human SIX5 gene, as a novel regulator of the development of a specific neuron, called RID. Our data support the role of unc-39 early in C. elegans development and suggest a possibility of complete absence of RID neuron in unc-39 mutants. unc-39 mutant has a similar locomotion phenotype to the RID-ablated animals, which provides further support to the hypothesis that the absence of RID contributes to the locomotion phenotype observed in the mutant. We show that unc-39 functions at multiple points in the lineage that gives rise to the RID neuron, and that its function is context-dependent.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 61-63).

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Feb. 13, 2009). Includes bibliographical references.

Thesis (Ph.D. in Biophysics & Genetics, Program in Molecular Biology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 115-132). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Embargoed. Vita. Bibliography: 196-214.

Though antibodies as therapeutics are limited to extracellular targets, their repertoire of molecular interactions has particular relevance to the many intracellular cellular proteins for which small molecule screening has reached impasse. For such proteins there is little recourse to theory, since molecular recognition is, in practical terms, still not well understood. Here I apply antibody discovery to the lysine demthylases KDM4D and PHF8, two proteins difficult to inhibit selectively due to the similarity of their binding pockets to those of the larger family. With a selective, picomolar affinity antibody, dependent on residues distal to the KDM4D active site, I present what is likely the first example of allosteric inhibition of a KDM4 lysine demethylase, demonstrating that there is opportunity outside active sites oversubscribed with pan inhibitors. Antibody discovery for PHF8, however, was plagued by a familiar problem: antibodies that bound when their antigen was immobilised directly to a surface, but barely bound at all when it was free in solution. The common explanation is that the partial denaturation that accompanies immobilisation reveals epitopes unavailable in solution, but examining the problem in detail for the Plant Homeodomain of PHF8 revealed a connection to its rarely sampled conformations. The prominence these antibodies in the immune responses to PHF8, and to some extent KDM4D, motivates two hypotheses on their origin: either the states are very immunogenic or there is a connection between states of irreversible damage and those sampled reversibly, but rarely, by a protein in solution.

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