ANALYSIS OF NEMATODE SEX DETERMINATION

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Our long-term goals are two-fold, (1) to understand, in genetic and molecular terms, the basis for the male/hermaphrodite decision in the nematode C. elegans and (2) to understand the mechanism of X chromosome dosage compensation at the genetic and molecular levels. The primary sex-determining signal in C. elegans is the X/A ratio; 2X/2A animals are hermaphrodite, and IX/2A animals are male. How the primary sex-determining signal is assessed and subsequently translated into the choice of either the hermaphrodite or male mode of sexual development re- mains a mystery, but is a primary focus of this grant. We have acquired significant insight into understanding the basis of the male/hermaphrodite decision by demonstrating that the sex determination and dosage compensation processes share common early steps prior to their divergence into two separate pathways. The hermaphrodite mode is coordinately controlled by at least two genes, sdc-I and sdc-2; the male mode is controlled by xol-l. The sdc genes appear to play a role in either assessing the X/A ratio or transmitting this signal to both the sex determination and dosage compensation pathways. Genetic interactions suggest that xol-l is the earliest acting gene in the known hierarchy that controls the male/hermaphrodite decision and is likely to be the gene nearest to the primary sex-determining signal. A fourth gene, dpy,-29, is also involved in controlling both processes, and illustrates a paradoxical feedback between dosage compensation disruptions and sex determination. Further insight into the male/hermaphrodite decision will be sought by: (1) Identification and analysis of additional genes central to both sex determination and dosage compensation. (2) A mosaic analysis of sdc-2, xol-l and dpy-29 to determine when the sex determination decision is made and whether it is a cell autonomous process or whether it involves factors extrinsic to the cell, such as diffusible products or cell-cell interactions. (3) An extensive molecular analysis of the genes that play a central role in the male/hermaphrodite decision, sdc-1, sdc-2, xol-l and dpy-29. The molecular analysis will include discerning how these genes are regulated in response to the X/A signal, (or how they help assess the X/A ratio), as well as how they regulate each other and the downstream sex determination and dosage compensation genes. The molecular characterization of these early-acting components of the sex determination decision will be the first molecular analysis of genes that control both processes in this organism. Further insight into the mechanism of X chromosome dosage compensation will be sought by: (1) Identification and analysis of additional dosage compensation genes. (2) Molecular characterization of two genes critical to the process, dpy-27 and dpy-28. This represents the first molecular characterization of dosage compensation genes in this organism. Elucidating the mechanism of sex determination will provide fundamental insight into developmental processes that go awry in human diseases.