Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Neuroscience." Includes bibliographical references (p. 224-234).

Thesis (Ph. D.)--University of Oregon, 2003. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 75-80). Also available for download via the World Wide Web; free to University of Oregon users.

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To understand the molecular basis of developmental control of cell division during C. elegans organogenesis, two different approaches were taken. First, a screen was performed to identify mutants with altered numbers of intestinal nuclei using a reporter transgene specific to the intestinal nuclei. The intestine displays three different cell division patterns; mitosis, karyokinesis and endoreplication, therefore, in this screen we could potentially isolate mutants in genes affecting any of these different cell cycles. An F2 semi-clonal screen was performed and mutants with fewer or supernumerary numbers of intestinal nuclei were isolated. One mutant, rr31, with twice the wild type complement of intestinal nuclei was mapped and the defect was subsequently shown to be due to a gain-of-function mutation in the cell cycle phosphatase cdc-25.1. Further characterization of the cdc-25.1(gf) mutant, showed that the extra intestinal cells arise from an additional division of the intestinal cell precursors during embryogenesis, and that this phenotype is unique to the intestinal lineage. (Abstract shortened by UMI.)

Mutations in the Caenorhabditis elegans maternal-effect gene clk-1 result in a highly pleiotropic phenotype, characterized by a general slow down in embryonic and larval development, as well as a slowing down of adult behaviors including defecation, pharyngeal pumping and swimming. First generation homozygous clk-1 mutants descended from a heterozygous mother are fully rescued for these mutant phenotypes. It has been shown that CLK-1 protein is a hydroxylase that acts in the conversion of demethoxyubiquinone (DMQ) to 5-hydroxyubiquinone, in the ubiquinone (Q) biosynthesis pathway. Consequently, clk-1 mutants accumulate the Q9 precursor, DMQ9 (the subscript refers to the length of the isoprenoid side chain). Here, I show that the profound maternal rescue observed in clk-1 maternally rescued animals is due to presence of the CLK-1 protein throughout larval development, in sufficient amounts to catalyze the production of Q9. clk-1 mutants have been shown to have a dietary requirement for Q8 due to their inability to synthesize Q9. I demonstrate that clk-1 maternally rescued animals have sufficient amounts of Q 9 to complete larval development and produce an almost full brood when raised on a Q8 deficient E. coli strain. I also show that prolonged arrest at the first larval stage, which is likely to result in degradation of any maternally contributed mRNA or protein, brings about a Clk mutant phenotype in maternally rescued animals. Finally, I reveal that the Clk mutant phenotype can be rescued at any larval stage by ectopic expression of CLK-1, suggesting that there is no developmental window for the rescue of clk-1 mutants by CLK-1. These results identify perdurance of maternally contributed product throughout development as the mechanism that accounts for the maternal effect observed in clk-1 mutants.

Several classes of genes determine the lifespan of the nematode Caenorhabditis elegans. Our laboratory is particularly interested in the clk class of genes that is composed of clk-1, clk-2, clk-3 , and gro-1. Mutations in these genes have been shown to extend lifespan and to deregulate several developmental and behavioural processes such as pharyngeal pumping and defecation cycle length. / clk-1 encodes a 187 amino acid mitochondrial protein that is composed of two homologous TRC domains (TRC for T&barbelow;andemly R&barbelow;epeated in C&barbelow;LK-1). Interestingly, the yeast homologue of clk-1, COQ7, has been implicated in ubiquinone biosynthesis. clk-1 (e2519) lesion is a point mutation that changes a conserved amino acid (E148K) in the second TRC domain. A structural model proposed that clk-1 is a di-iron carboxylate protein. We found that mutations in the di-iron binding center abolish CLK-1 activity and modify the subcellular distribution of CLK-1 in clk-1( qm30) null mutants.