Sex determination and differentiation in C elegans

C. elegans is an androdioecious species. As shown in Fig. 1.1A, its two sexes are hermaphrodite and male. The hermaphrodite is essentially a modified female that produces and stores some sperm that can be used to self-fertilize its own oocytes. Animals of this sex lack male genital structures; thus, C. elegans hermaphrodites are unable to cross-fertilize each other. In contrast, the male produces only sperm, and males can reproduce only by cross-fertilizing a hermaphrodite. Hermaphroditism is a recent evolutionary innovation in C. elegans, as its nearest phylogenetic neighbors are gonochoristic (i.e., malefemale) species (Kiontke et al., 2004), indicating that the hermaphrodite is generated from minor modification of an ancestral female developmental program. In self-fertilizing hermaphrodite populations, males arise very infrequently (<0.3%). Despite the relative rarity of the male, its developmental program is maintained in the genome, indicating that males may be required to provide outcrossing. However, the rate of outcrossing in wild populations seems to be very low, and over evolutionary time the role of males in the species may be dwindling (Barriere and Felix, 2005; Chasnov and Chow, 2002; Stewart and Phillips, 2002). Owing to its ability to self-fertilize, the hermaphrodite offers experimental advantages that have led to a much more thorough characterization of its neuroanatomy and development; in several regards, the biology of the C. elegans male is much less well understood than that of the hermaphrodite.

As in most animals, sex determination in C. elegans is chromosomal: embryos with two sex chromosomes (XX) develop as hermaphrodites; those with only one (X0) become males (Brenner, 1974; Nigon and Dougherty, 1949). There is no heteromorphic (Y) sex chromosome in C. elegans. Interestingly, the number of X chromosomes per se is not the primary sex-determining cue; rather, the sex chromosome to autosome ratio X:A is assessed according to the relative copy numbers of specific autosomal and sex chromosome "signal element" genes (Carmi et al., 1998; Madl and Herman, 1979; Powell et al., 2005). Downstream of these signal element genes lies a complex regulatory hierarchy that independently controls both dosage compensation (the reduction of gene expression from each hermaphrodite X chromosome by half) (reviewed by Meyer, 2005) and sexual differentiation (Fig. 1.1B). This latter pathway relies on successive repressive interactions to control the activity of the gene tra-1, the master sexual regulator in C. elegans. XX animals carrying a null mutation in tra-1 develop as somatic males, whereas X0 animals are essentially unaffected, indicating that tra-1 functions in hermaphrodites to promote female and/or repress male fates (Hodgkin, 1987; Hodgkin and Brenner, 1977). tra-1 also has a role in the development of the gonad

Rounded tail tip

Sperm Male tail sensilla (rays, hook, post-cloacal sensilla, spicules)

X signal elements fox -1 sex-1

sea sea-2 sea-3

k 3r xol-1

A signal elements sdc -1 I sdc-2-sdc-3

tra-3

tra-2

Dosage compensation sel-10

fem-1

fem-3

Hermaphrodite Male

Figure 1.1. Sex determination and differentiation in C. elegans. (A) The primary sexual dimorphisms in C. elegans. Adult hermaphrodites (above) are XX and have a tapered, whiplike tail, a vulva, and a bilobed gonad that produces both oocytes and sperm. Adult males (below) are X0, slightly smaller in size, and have a rounded tail tip, several classes of tail sensilla, and a single-armed gonad that makes sperm. Modified from Zarkower (2006). (B) The somatic sex determination pathway. The X:A ratio is read by signal-element genes on the X chromosomes and autosomes; these converge onto the regulator xol-1, which is active only in X0 animals (Rhind et al., 1995). Downstream of the sdc genes, dosage compensation (not shown) reduces gene expression from the X chromosome by half and is controlled independently from the differentiation of somatic characteristics (Meyer, 2005). Essentially all somatic characteristics are controlled through a series of repressive interactions that regulate the master sex-determining gene tra-1. In XX animals, tra-1 is ON, repressing male fates and perhaps promoting hermaphrodite fates. In X0 animals, tra-1 is OFF, allowing male development to proceed.

in both sexes; this is thought to be an ancestral function that is separate from the role of tra-1 in sex determination (Hodgkin, 1987; Mathies et al., 2004). Interestingly, neither tra-1 nor its upstream regulators have conserved functions in sex determination outside nematodes, consistent with the idea that upstream events in sex determination evolve rapidly (Wilkins, 1995; Zarkower, 2001).

Through alternative splicing, tra-1 encodes two Zn-finger proteins with sequence similarity to Ci/GLI transcription factors, indicating that a hedgehoglike pathway may have been co-opted in the worm to carry out a sex determination function (Zarkower and Hodgkin, 1992). The longer of these forms, called TRA-1A, is thought to be the active form, as the shorter is unable to bind DNA in vitro (Zarkower and Hodgkin, 1993). TRA-1A has been shown to act as a transcriptional repressor to block the expression of male-specific genes in XX animals (Conradt and Horvitz, 1999; Yi et al., 2000); TRA-1A may also act to promote hermaphrodite gene expression. Genetic analysis has suggested that the sex-specific regulation of tra-1 activity comes about posttranslationally (de Bono et al., 1995). Consistent with this, it has been found that sex-specific proteolysis may be critical in generating a hermaphrodite-specific active form of TRA-1A (Schvarzstein and Spence, 2006). The mechanisms by which the fem genes, the most downstream genetic regulators of tra-1, control sex-specific TRA-1A activity remain an area of active investigation.

Elegant genetic studies have shown that tra-1 acts cell-autonomously in the specification of nearly all sexually dimorphic cell fates in the C. elegans soma (Hunter and Wood, 1990). This stands in stark contrast to vertebrate sex determination mechanisms, in which sex determination events in the early gonad conscript peripheral tissues to adopt sex-specific characteristics through the influence of gonadal steroids (Morris et al., 2004). In C. elegans, most sex-specific extragonadal characteristics do not depend on the gonad, and gonadal precursor cells can be completely removed by laser ablation very early in development with essentially no effect on sex-specific somatic development (Kimble, 1981; Klass et al., 1976). Instead of relying on a gonadal cue, the sexual fate of somatic cells in C. elegans begins with cell-autonomous establishment of the X:A ratio early in embryonic development (Rhind et al., 1995). A series of repressive interactions reinforces this decision, leading to local non-cell-autonomous activity of the secreted protein HER-1, which acts through the FEM proteins to regulate TRA-1A activity (Hodgkin, 1986; Hunter and Wood, 1992). Thus, the status of TRA-1A activity in any given somatic cell is sufficient to determine whether that cell adopts a male (tra-1 OFF) or hermaphrodite (tra-1 ON) fate. The only known exception to this is the hermaphrodite vulva, whose development relies on an inductive signal from the hermaphrodite somatic gonad (Hunter and Wood, 1992; reviewed by Sternberg, 2005).

Therefore, the genes repressed or activated by TRA-1A are thought to wholly account for the somatic characteristics that distinguish hermaphrodites from males, although recent evidence has suggested that there may be some relatively minor tra-1 -independent functions that are necessary for the full complement of sex-specific differences (Grote and Conradt, 2006; van den Berg et al., 2006). While some genes downstream of tra-1 are known, the genetic mechanisms that link tra-1 to sex-specific differentiated characteristics—particularly in the nervous system—remain incompletely described. As described below, two genes controlled by tra-1, egl-1 and ceh-30, regulate the sexual phenotype of the nervous system by controlling sex-specific programmed cell death. The Hox genes mab-5 and egl-5 are also regulated at least indirectly by tra-1 and have important roles in shaping male-specific cell lineages and neural cell fates (Chisholm, 1991; Chow and Emmons, 1994; Costa et al., 1988; Kenyon, 1986). Finally, three related genes, mab-3, mab-23, and dmd-3, control partially overlapping subsets of male-specific development and function in the nervous system and elsewhere, though their relationship to tra-1 is complex and not fully understood (Lints and Emmons, 2002; Shen and Hodgkin, 1988; D. A. Mason, K. H. Lee, R. M. Miller, and D. S. P., unpublished data). As mentioned above, these genes encode proteins harboring one or more DM (doublesex/mab-3) domains, the only known conserved molecular link between effectors of sex determination in metazoans (reviewed in Zarkower, 2001). The importance of these factors in the sexual differentiation of the C. elegans nervous system has led to speculation about the potential for the vertebrate relatives of these genes, the DMRT family, to be regulators of sexual dimorphism in the central nervous system (CNS).

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