Analysis of Nematode Sex Determination

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): Dose-sensitive signals play essential roles in cell fate decisions during development. One area of our research investigates mechanisms by which small quantitative differences in molecular signals are translated into dramatically different developmental fates. One of our long-term goals is to dissect the quantitative signals and the genetic switch that specifies sexual fate in the nematode C. elegans. C. elegans determines sex by tallying X-chromosome number relative to the ploidy, the sets of autosomes (X:A signal). We showed that a set of genes on X, called X signal elements (XSEs), relays X-chromosome dose by repressing the activity of the sex determination switch gene xol-1 through both transcriptional and pre-mRNA mechanisms. Another set of genes called autosomal signal elements (ASEs) communicates ploidy by antagonizing the XSEs to activate xol-1. xol-1 specifies the male fate when active and the hermaphrodite fate when inactive. Our work investigates molecular mechanisms by which XSEs and ASEs antagonize each other to determine sex. One XSE is a nuclear hormone receptor (NHR) called SEX-1, a homolog of the retinoic acid receptor (RAR) gene family that participates in signaling pathways used for patterning and cellular differentiation in all metazoans. Disruptions in RARs are associated with human cancers, knowledge that has lead to the use of retinoids in the treatment of leukemias. Information gained from model organisms such as C. elegans about the genetic pathways in which NHRs function will provide an opportunity to discover other gene targets for drug therapy, which might be applicable to humans. A second long-term goal is understand the mechanism of X-chromosome dosage compensation, which equalizes X expression between the sexes. We defined a protein complex (DCC) that binds both X chromosomes of XX animals to repress X expression by half. Members of the complex also play essential roles in the compaction, resolution, and segregation of mitotic and meiotic chromosomes as well as the control of genetic recombination between homologous meiotic chromosomes. Not only is the protein complex essential for proper gene expression and viability, most components are essential for genome stability. Thus, studying dosage compensation will help us understand genomic instability caused by errors in chromosome segregation and disruption of meiotic recombination. We have identified cis-acting regulatory elements that target the X chromosome for repression by the DCC and discovered fundamental principles by which the DCC recognizes and binds X. Our future work will explore the connection between chromosome structure, DCC binding, and chromosome-wide gene repression.