The general goal of this work is to understand how cell division, differentiation and survival are regulated in response to extracellular and intracellular signals. The specific focus of this work is to determine how these phenomena are regulated within the gonad of the nematode, Caenorhabditis elegans. The work described in this proposal will focus on a set of genes that mediate the response of the somatic gonad progenitor cells to growth regulatory signals. Two genes, gon-2 and gon-11, have been identified that are required for gonadal cell divisions, beginning in the first larval stage. gon-2 encodes a predicted protein of the TRP cation channel family. The molecular identity of gon-11 is not yet known. In addition, four different gem (gon-2 extragenic modifier) loci have been identified by screening for revertants of the temperature-sensitive allele, gon-2(q388). A convergent line of work has resulted in the discovery of a new gene, neg-1, mutation of which leads to pleiotropic defects that include necrotic death of the gonadal precursor cells. neg-1 and weak alleles of gon-2 can be suppressed by increasing the level of magnesium in the medium. However, gon-11 and strong alleles of gon-2 show little or no suppression by increased magnesium levels. gon-2 is proposed to be expressed within the somatic gonadal cells, where it is activated in response to developmental signals and mediates the influx of Mg2+ and Ca2+ These cations would then act in combination to promote cell division and maintain cell viability. The activity and downstream effects of gon-2 are regulated by the gem loci, gon-11 and neg-1. There has been no genetic analysis of how LTRP channels are regulated or how they control cell proliferation/viability. Similarly, there has been no genetic analysis of the regulation of metazoan development in response to the increases in intracellular Mg2+ and Ca2t Therefore, this work will provide a framework for understanding which cellular components are involved in the regulation of LTRP activity and how cells respond to increases in intracellular Mg2+ and Ca2+. The molecules that regulate cell division in response to extracellular signals have been well conserved evolutionarily and aberrancies in their regulation contribute to the onset of cancer in humans. Therefore, the results of this work are likely to be highly significant with regard to the etiology of human disease.
