In the nematode Caenorhabditis elegans, sex is determined by the ratio of X chromosomes to sets of autosomes: XX animals (2X:2A1.0) develop as hermaphrodites and XO animals (1X:2A0.5) develop as males. TRA-1, the worm ortholog of Drosophila Cubitus interruptus and mammalian Gli (Glioma-associated homolog) proteins, is the terminal transcription factor of the C. elegans sex-determination pathway, which specifies hermaphrodite fate by repressing male-specific genes. Here we identify a consensus TRA-1 binding site in the regulatory region of xol-1, the master switch gene controlling sex determination and dosage compensation. xol-1 is normally expressed in males, where it promotes male development and prevents dosage compensation. We show that TRA-1 binds to the consensus site in the xol-1 promoter in vitro and inhibits the expression of xol-1 in XX animals in vivo. Furthermore, inactivation of tra-1 enhances, whereas hyperactivation of tra-1 suppresses, lethality in animals with elevated xol-1 activity. These data imply the existence of a regulatory feedback loop within the C. elegans sex-determination and dosagecompensation cascade that ensures the accurate dose of X-linked genes in cells destined to adopt hermaphrodite fate.

Females and males differ substantially in various neuronal functions in divergent, sexually dimorphic animal species, including humans. Despite its developmental, physiological and medical significance, understanding the molecular mechanisms by which sex-specific differences in the anatomy and operation of the nervous system are established remains a fundamental problem in biology. Here, we show that in Caenorhabditis elegans (nematodes), the global sex-determining factor TRA-1 regulates food leaving (mate searching), male mating and adaptation to odorants in a sex-specific manner by repressing the expression of goa-1 gene, which encodes the Gα (i/o) subunit of heterotrimeric G (guanine-nucleotide binding) proteins triggering physiological responses elicited by diverse neurotransmitters and sensory stimuli. Mutations in tra-1 and goa-1 decouple behavioural patterns from the number of X chromosomes. TRA-1 binds to a conserved binding site located in the goa-1 coding region, and downregulates goa-1 expression in hermaphrodites, particularly during embryogenesis when neuronal development largely occurs. These data suggest that the sex-determination machinery is an important modulator of heterotrimeric G protein-mediated signalling and thereby various neuronal functions in this organism and perhaps in other animal phyla.

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