The Caenorhabditis elegans Gene sdc - 2 Controls Sex Determination and Dosage Compensation in X X Animals Chad Nusbaum and Barbara

We have identified a new X-linked gene, sdc-2, that controls the hermaphrodite (XX) modes of both sex determination and X chromosome dosage compensation in Caenorhabditis elegans. Mutations in sdc-2 cause phenotypes that appear to result from a shift of both the sex determination and dosage compensation processes in XX animals to the X 0 modes of expression. Twenty-eight independent sdc2 mutations have no apparent effect in X 0 animals, but cause two distinct phenotypes in XX animals: masculinization, reflecting a defect in sex determination, and lethality or dumpiness, reflecting a disruption in dosage compensation. The dosage compensation defect can be demonstrated directly by showing that sdc-2 mutations cause elevated levels of several X-linked transcripts in XX but not X0 animals. While the masculinization is blocked by mutations in sex determining genes required for male development (her-1 and fern-3), the lethality, dumpiness and overexpression of X-linked genes are not, indicating that the effect of sdc-2 mutations on sex determination and dosage compensation are ultimately implemented by two independent pathways. We propose a model in which sdc-2 is involved in the coordinate control of both sex determination and dosage compensation i XX animals and acts in the regulatory hierarchy at step prior to the divergence of the two pathways. T HE strategies that various organisms use to determine sexual fate are diverse, ranging from schemes in which sex is specified by a chromosomal mechanism to those in which sex is determined by environmental conditions (BULL 1983). For organisms whose choice of sexual fate is specified chromosomally, a variety of mechanisms exist. These include mechanisms of the type used in Drosophila melanogaster (XU male/XX female: BRIDGES 1925) and Caenorhabditis elegans ( X 0 male/XX hermaphrodite: MADL and HERMAN 1979), in which the X/A ratio (ratio of sex chromosomes to sets of autosomes) serves as the primary sex determining signal. In other organisms, a dominant sex chromosome typified by the Y chromosome in mammals (XU male/XX female) is the primary determinant of sexual fate. In each of these cases, the sex determining mechanism causes the two sexes to differ in the number of sex chromosomes. For organisms that have evolved a dosage compensation mechanism to equalize sex-linked gene expression, the question arises as to whether the sex determination and dosage compensation processes are coordinately controlled. In mammals the sex determination and dosage compensation processes are initiated independently, since the signal for sex determination depends on a region of the Y chromosome (reviewed in MCLAREN 1988), while X inactivation is triggered in response to the number of X chromosomes (reviewed in GRANT and CHAPMAN 1988). In contrast, the two processes are linked in D. melanoGenetics 122 579-593 (July, 1989) gaster; the choice of sexual fate and the level of Xlinked gene expression are established by the activity state of the Sxl gene (CLINE 1979, 1983, 1984). In C. elegans both the choice of sexual fate and the level of X chromosome expression appear to be triggered in response to the same primary signal, the X/A ratio (VILLENEUVE and MEYER 1987; MILLER et al. 1988; reviewed in MEYER 1988). Mutations in single genes can simultaneously disrupt both sex determination and dosage compensation, inappropriately shifting both processes to either the male mode in XX animals, or to the hermaphrodite mode in X0 animals. Thus the sex determination and dosage compensation pathways share common steps prior to their divergence into independent pathways. Two genes, sdc-1 and xol-1, are involved in the coordinate control of these two processes. xol-1 controls the male mode of both sex determination and dosage compensation in X0 animals (MILLER et al. 1988). Mutations in xol-1 shift both processes toward their XX modes of expression, resulting in the feminization and death of X 0 animals. The lethality is presumably caused by the inappropriately low X chromosome expression measured in dying xol-1 X0 animals. sdc-1, in contrast, is required for the hermaphrodite mode of both processes (VILLENEUVE and MEYER 1987). sdc-1 mutations cause masculinization and elevated levels of X-linked transcripts in XX animals, but have no apparent effect