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Riddle DL, Blumenthal T, Meyer BJ, et al., editors. C. elegans II. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.

Cover of C. elegans II

C. elegans II. 2nd edition.

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Section IVHermaphrodite-Specific Genes that Coordinately Control Sex Determination and Dosage Compensation

The target of the worm X:A signal, xol-1 , coordinately controls sex determination and dosage compensation through its negative regulatory effects on another coordinate control switch gene (Fig. 3). This gene, sdc-2 , functions exclusively in hermaphrodites and requires the participation of at least two other coordinate control genes, sdc-1 and sdc-3 , to activate the hermaphrodite mode of sex determination and dosage compensation (Villeneuve and Meyer 1987, 1990b; Nusbaum and Meyer 1989; DeLong et al. 1993).

Figure 3. Regulatory hierarchy that controls somatic sex determination and differentiation in hermaphrodites and males.

Figure 3

Regulatory hierarchy that controls somatic sex determination and differentiation in hermaphrodites and males. Genes in the regulatory cascade that are functionally active are boxed and boldfaced. A dark (more...)

The first sdc-2 mutation was recovered in a screen for X-linked, hermaphrodite-specific lethal mutations, and subsequent alleles were recovered as suppressors of xol-1 XO-specific lethality (Nusbaum and Meyer 1989). Although null sdc-2 alleles have no effect on otherwise wild-type XO worms, in XX animals, they cause complete reversal of sexual fate, similar to mutations in the hermaphrodite sex-determination switch gene tra-1 , and cause extensive (>95%) XX-specific lethality, similar to mutations in the dosage compensation dpy genes. Direct measurement of X-linked transcript levels confirmed that sdc-2 mutations disrupt dosage compensation and cause elevated X-linked transcript levels in XX animals but not in XO animals.

The effects of sdc-2 mutations on sex determination and dosage compensation are implemented by independent pathways (Nusbaum and Meyer 1989). This point is illustrated by the fact that masculinization but not lethality is blocked by a mutation in her-1 , a male-specific switch gene that heads the sex determination branch of the regulatory hierarchy. The functioning of sdc-2 as a negative regulator of her-1 was shown more directly by the fact that in sdc-2 XX mutants, her-1 transcripts are present at the level normal for males but not for hermaphrodites (Trent et al. 1991). sdc-2 could not be positioned in the dosage compensation hierarchy by such epistasis analysis since mutations in sdc-2 and the dosage compensation dpy genes have the same effect on dosage compensation. A position for sdc-2 upstream of the dpy genes could be inferred from the fact that sdc-2 controls both sex determination and dosage compensation, whereas the dpy genes have a direct effect only on dosage compensation. Recent molecular experiments (see below) confirm this placement and demonstrate that SDC-2 is sex-specifically localized to the hermaphrodite X chromosomes (D. Lapidus et al., unpubl.) and activates dosage compensation by localizing the dosage compensation DPY proteins to the hermaphrodite X chromosomes (Chuang et al. 1996; Lieb et al. 1996).

Recent experiments also demonstrate that sdc-2 is a hermaphrodite switch gene (H. Dawes et al., unpubl.). Antibody staining revealed that SDC-2 is made exclusively in XX animals, confirming that the sdc-2 gene is regulated by the X:A signal. Moreover, ectopic expression of sdc-2 transcripts in XO animals causes extensive (~90%) XO-specific lethality that is suppressed by XX-specific dosage compensation mutations. Many rescued XO animals develop as hermaphrodites. These results indicate that the death of XO animals induced by ectopic SDC-2 is a consequence of dosage compensation upsets. From the switch nature of sdc-2 and its exclusively zygotic expression, it seems likely that sdc-2 is the target for negative regulation by xol-1 in males to prevent activation of dosage compensation and hermaphrodite sexual development. In support of this hypothesis, an extrachromosomal array carrying numerous copies of a truncated sdc-2 gene was found to have no adverse effect on males because it made no functional sdc-2 gene product, yet it partially suppressed the XX-specific lethality caused by overproduction of xol-1 transcripts (Rhind et al. 1995). The truncation left intact the 5′ sdc-2 regulatory region and three fourths of the structural gene; hence, that portion of the sdc-2 gene may contain the xol-1 target. SDC-2 is a very large protein (350 kD) with no similarity to sequences in current databases (D. Berlin et al., unpubl.). Although sdc-2 initiates all aspects of hermaphrodite development, it is not yet known whether it is involved in maintaining that developmental mode.

The first gene to be discovered that demonstrated the link between sex determination and dosage compensation was sdc-1 (Villeneuve and Meyer 1987, 1990b). It acts at the same place in the hierarchy as sdc-2 , but it is maternally rescuable and its null phenotype is relatively weak: Not all XX animals are masculinized, and the masculinization itself is incomplete. Moreover, null sdc-1 alleles cause no significant XX-specific lethality, despite causing overexpression of X-linked genes. Nevertheless, there is synergism between alleles of sdc-1 and sdc-2 that demonstrates the importance of their joint participation in development. The combination of a weak sdc-2 allele that causes little or no lethality by itself and a null sdc-1 allele that is also nonlethal results in complete XX-specific lethality. Temperature-shift experiments demonstrated that sdc-1 is required in the first half of embryogenesis for proper sex determination and for establishing the XX mode of dosage compensation. Consistent with a role for sdc-1 as a negative regulator of her-1 transcription, the gene encodes a 139-kD protein that contains seven zinc finger motifs of the TFIIIA variety and may therefore be a DNA-binding protein (Nonet and Meyer 1991).

Another partner for sdc-2 is sdc-3 . The intimate relationship between these two genes is dramatically illustrated by the fact that the localization of SDC-2 protein to the hermaphrodite X chromosomes requires sdc-3 activity (H. Dawes et al., unpubl.), and conversely, localization of SDC-3 to X requires sdc-2 (T.L. Davis and B.J. Meyer, in prep.). The stability and/or synthesis of SDC-3 is reduced by mutations in sdc-2 .

Analysis of sdc-3 was complicated by its unusual genetic properties, which nevertheless ultimately shed considerable light on its function (DeLong et al. 1993). This gene differs from the other coordinate control genes in that its sex determination and dosage compensation activities are separately mutable, indicating that they function independently. Three different classes of mutant sdc-3 alleles were identified genetically. One class disrupts sex determination, causing masculinization of XX animals, but has no obvious effect on dosage compensation. The masculinized XX animals have levels of her-1 transcripts appropriate for XO animals, indicating that sdc-3 , like the other two sdc genes, represses her-1 in hermaphrodites. A second class disrupts dosage compensation and causes greater than 95% XX-specific lethality but has little or no effect on sex determination. These two classes of mutations complement each other as if they represent two separate genes. However, a third class composed of true null alleles fails to complement alleles in either of the first two classes, indicating that all three classes are defective in the same gene. Ironically, the null phenotype itself is misleading, since it does not reflect the gene's involvement in sex determination: Escapers are not masculinized. Extensive genetic and molecular analyses revealed that the dosage compensation defect of sdc-3 null alleles suppresses their own sex determination defect as a consequence of a feedback between sex determination and dosage compensation as discussed below.

Molecular analysis of sdc-3 (Klein and Meyer 1993) confirmed the genetic conclusions and revealed that the sex determination mutations cluster to a region of the 250-kD SDC-3 protein that has limited homology with the ATP-binding domain of myosin, whereas dosage compensation mutations eliminate a pair of TFIIIA zinc finger motifs at the carboxyl terminus. Null mutations all abort translation of the SDC-3 protein prior to its sex determination and dosage compensation domains. The zinc finger motifs are essential for the localization of SDC-3 to X for dosage compensation (T.L. Davis and B.J. Meyer, in prep.). The mechanism by which SDC-3 represses her-1 in sex determination is not yet known.

Copyright © 1997, Cold Spring Harbor Laboratory Press.
Bookshelf ID: NBK20191
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