Normal Hermaphroditism in Nematodes and Fish

Hermaphroditism in the Nematode C. elegans

The nematode Caenorhabditis elegans usually has two sexual types: hermaphrodite and male. Most individuals of this species are hermaphroditic, having both testes and ovaries. As larvae, these hermaphrodites make sperm, which is stored in the nematode’s genital tract (Figure 8.42 in Gilbert, 2000). The adult ovary produces eggs, and these eggs become fertilized as they migrate into the uterus. (The sperm is already present in the hermaphroditic adult.) Self-fertilization almost always produces more hermaphrodites. Only 0.2 percent of the progeny are males. These males, however, can mate with hermaphrodites; and because their sperm has a competitive advantage over endogenous hermaphroditic sperm, the sex ratio resulting from such matings is about 50 percent hermaphrodites to 50 percent males (Hodgkin, 1985).

In C. elegans, the hermaphrodite is XX and the male is XO. As in Drosophila, sex is determined by the ratio of X chromosomes to autosomes. In closely related species of nematodes, XX females are found, suggesting that the hermaphrodites evolved from females. Somatically, the females and hermaphrodites are identical, the only difference being that the hermaphrodites make sperm during their early development before switching over to egg production. In C. elegans, there even exists a dominant mutation (tra-1D) that transforms XX or XO individuals into fertile females. In colonies with such an allele, three sexes are possible and functioning (Hodgkin, 1980).

As in Drosophila, sex determination in C. elegans involves a pivotal gene that reads and responds to the X:A ratio. The gene that integrates the numerators and denominators of C. elegans development is xol-1 (XO-lethal), an X-linked gene that is inhibited by the products of two other X-linked genes, sex-1 and fox-1 (Carmi et al., 1999; Hansen and Pilgrim, 1999). High levels of XOL-1 during gastrulation turn off the pathway for hermaphroditic development, thereby turning the animal into a male (Rhind et al., 1995). XOL-1 appears to accomplish this by repressing the sdc (sex determination control) genes, whose activities make the animal a hermaphrodite (Miller et al., 1988).

The pathway for C. elegans sex determination was deciphered by finding mutations in genes necessary for hermaphrodite development (the tra genes), as well as others necessary for the expression of the male phenotype (the her and fem genes). By creating genotypes carrying different combinations of these mutations, Hodgkin (1980) and others were able to construct a model for this developmental pathway (Figure 1). For instance, tra-2 mutations all suppressed the her-1 mutation, indicating that her-1 is later in the pathway.

The crucial gene in the pathway for sex determination appears to be tra-1. If the wild-type tra-1 gene is active, the individual is a hermaphrodite. If tra-1 is not functional, the individual is a male. The other genes appear to regulate this single switch gene.

Figure 1
Figure 1   Figure 1. Schematic model of somatic sex determination in C. elegans. The sdc-1 gene is postulated to be involved in transmitting the X/A ratio. It controls X chromosome dosage compensation as well as suppressing the her-1 gene if the ratio is 1. The high/low designation reflects functional gene activity. The activity of the sdc genes eventually leads to the activity of the tra-1 gene, whose activity promotes the hermaphroditic phenotype. The scd genes can be inhibited by the xol gene, which is only active in XO (males). (After Hodgkin, 1985; Miller et al., 1988.)

But what does this linear genetic pathway have to do with the actual cellular events leading to sex determination? Recent studies indicate that some of these genes encode proteins of a signaling pathway between cells. Analysis of genetic mosaics suggests that sdc-1 and her-1 are not necessarily acting in the cells that make them. Rather, these genes appear to make secreted products. In contrast, tra-1 acts in a cell-autonomous fashion and is, therefore, likely to be part of a signal-receiving apparatus. The sequence of the tra-1 gene suggests that it encodes a zinc finger transcription factor (Hunter and Wood, 1990; Zarkower and Hodgkin, 1992; Perry et al., 1993). Kuwabara and Kimble (1992) have recently proposed a model that integrates this genetic pathway with the cellular biology of sex determination. The her-1 protein is thought to promote male development in XO nematodes by inhibiting tra-2. The protein encoded by tra-2, however, is not a transcription factor or a splicing factor, but an integral membrane protein with multiple transmembrane domains. Moreover, its mRNA is found (in different amounts) in both males and females. According to this speculative model (Figure 2), the fem proteins combine to create one large fem protein complex, and this complex is bound by the tra-2 membrane protein. In XX individuals, the fem protein complex is bound to the membrane, and the tra-1 protein can enter the nucleus. In XO nematodes, however, the her-1 protein binds to the extracellular region of the tra-2 protein, causing the tra-2 protein to release the fem complex. This fem complex, once free in the cytoplasm, can bind the tra-1 protein and prevent its entering the nucleus. Since the tra-1 protein (a putative transcription factor) cannot enter the nucleus, it cannot activate the hermaphrodite-specific genes. More studies need to be done to confirm or disprove this model, but it is useful both for suggesting new research and for visualizing how the genes might generate the pathway for sex determination in C. elegans.

Figure 2
Figure 2   Hypothetical scheme for the actions of sex-determining genes in C. elegans. In XX individuals, the fem proteins are sequestered near the cell membrane by the products of the tra-2 genes. In the absence of the fem proteins, tra-1 protein enters the nucleus to transcribe genes needed for hermaphroditic development. In XO individuals, the her-1 protein binds to the tra-2 product, causing the tra-2 product to release the fem proteins. Once free in the cytoplasm, the fem proteins can bind the tra-1 product, preventing it from entering the nucleus. (After Kuwabara and Kimble, 1992.)

One of the most interesting problems of C. elegans is its hermaphroditism. How did such a condition arise in an organism that probably had a male/female sex system? What gene changes arose, and were there other solutions that could have prevailed? The sex-determining genes of the closely related species C. ramanei (with male and female individuals) are now being identified so that such questions may be answered (see Haag and Kimble, 2000).

Hermaphroditism in Fishes

While hermaphroditism is not uncommon in worms and insects, it is rarely seen in vertebrates. In birds and mammals, hermaphroditism is usually a pathological condition causing infertility. The most common vertebrate hermaphrodites are fishes, which display several types of hermaphroditism (Yamamoto, 1969). Some fishes, however, are gonochoristic; that is, they have a chromosomally determined sex that is either male or female. Hermaphroditic fish species can be divided into three groups. The first are the synchronous hermaphrodites, in which ovaries and testicular tissues exist at the same time and in which both sperm and eggs are produced. One such species is Servanus scriba. In nature and in aquaria, these fish form spawning pairs. As soon as one of the fish spawns its eggs, the other fish fertilizes them. Then the fish reverse their roles, and the fish that was formerly male spawns its eggs so that they can be fertilized by the sperm of its partner (Clark, 1959).

In other hermaphroditic species, an individual undergoes a genetically programmed sex change during its development. In these cases, the gonads are dimorphic, having both male and female areas. One or the other is predominant during a certain phase of life. In protogynous ("female-first") hermaphrodites, an animal begins its life as a female, but later becomes male. The reverse is the case in protandrous ("male-first") species. Figure 3 shows the gonadal changes of the protandrous hermaphroditic fish Sparus auratus. At first, testicular tissue predominates, but after a transition period during which both testicular and ovarian tissues are seen, the ovarian cells take over.

Figure 3
Figure 3   Gonadal changes in the hermaphroditic fish Sparus auratus, shown in section through the gonad of (A) the male phase, (B) the transitory phase, and (C) the final, female phase. (Courtesy of the family of T. Yamamoto.)

Literature Cited

Carmi, I., Kopczynski, J. B., and Meyer, B. J. 1999. The nuclear hormone receptor SEX-1 is an X-chromosome signal that determines nematode sex. Nature 396: 173.

Clark, E. 1959. Functional hermaphroditism and self-fertilization in a serranid fish. Science 129: 215-216.

Haag, E. S. and Kimble, J. 2000. Regulatory elements required for development of Caenorhabditis elegans hermaphrodites are conserved in the tra-2 homologue of C. remanei, a male/female sister species. Genetics 155: 105-116.

Hansen, D. and Pilgrim, D. 1999. Sex and the single worm: sex determination in the nematode C. elegans. Mech. Devel. 83: 3-15.

Hodgkin, J. 1980. More sex-determination mutants of Caenorhabditis elegans. Genetics 96: 649-664.

Hodgkin, J. 1985. Males, hermaphrodites, and females: Sex determination in Caenorhabditis elegans. Trends Genet. 1: 85-88.

Hunter, C. P. and Wood, W. B. 1990. The tra-1 gene determines sexual phenotype cell-autonomously in C. elegans. Cell 63: 1193-1204.

Kuwabara, P. E. and Kimble, J. 1992. Molecular genetics of sex determination in C. elegans. Trends Genet. 8: 164-168.

Miller, L. M., Plenefisch, J. D., Casson, L. P. and Meyer, B. 1988. xol-1: A gene that controls the male mode of both sex determination and X chromosome dosage compensation in C. elegans. Cell 55: 167-183.

Rhind, N. B., Miller, L. M., Kopczynski, J. B. and Meyer, B. J. 1995. xol-1 acts as an early switch in the C. elegans male/hermaphrodite decision. Cell 80: 71-82.

Yamamoto, T.-O. 1969. Sex differentiation. In W. S. Hoar and D. J. Randall (eds.), Fish Physiology, Vol. 3. Academic Press, New York, pp. 117-175.

Zarkower, D. and Hodgkin, J. 1992. Molecular analysis of the C. elegans sex-determining gene tra-1: A gene encoding two zinc finger proteins. Cell 70: 237-249.

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