determinatIntroduction to sex ion*
C. elegans has two sexes, hermaphrodite and male. The hermaphrodite is a modified female that in the fourth
larval stage makes and stores sperm to be used later to fertilize oocytes produced within the gonad of the same
animal after spermatogenesis is finished. The embryos produced by self-fertilization are encased in an egg shell and
initiate development within the uterus of the hermaphrodite. When they reach about the 30-cell stage, the
egg-embryos are laid by the hermaphrodite through a vulva. A useful consequence of this mode of reproduction is
that a single hermaphrodite heterozygous for a recessive gene automatically generates one-quarter recessive
homozyotes in its brood of self progeny—a feature, shared with Mendel's peas, that helped attract Sydney Brenner
to the worm in the first place. At the same time, Brenner saw that males, which can mate with and transfer their
sperm to hermaphrodites to produce cross progeny, are useful to the experimentalist for making new combinations
of genes. Presumably this is also why C. elegans has retained the male sex, which in the short term at least is
completely dispensable for reproduction.
Hermaphrodites are normally diploid, with five pairs of autosomes and two X chromosomes. Males have the
same five pairs of autosomes but only a single X chromosome. Nearly all gametes—sperm and eggs—produced by
hermaphrodites are haplo-X and thus give rise to XX hermaphrodite self progeny, but rare males are generated
through spontaneous X chromosome loss. Males produce equal numbers of haplo-X and nullo-X sperm, so that half
of the cross progeny they sire will also be male.
Males and hermaphrodites are distinctly different creatures. The first three chapters in this section describe, at
the level of individual cells, the major differences between the sexes and how they arise developmentally. The
embryonic cell lineages in the two sexes are essentially identical, although a few cells in each sex are programmed
to die sex-specifically during late embryogenesis; for example, males get rid of two cells that in hermaphrodites
would become neurons required for egg-laying. But most differences between the sexes arise during postembryonic
development through different patterns of cell lineage. Surprisingly, the different patterns of lineage and
differentiation are driven largely by the same genes in the two sexes, although by different cell-specific patterns of
gene expression. The same multiple transcription factors and core set of intercellular signal transduction systems are
used repeatedly in the sex-specific developmental pathways of both sexes.
In the first chapter of this section, Scott Emmons describes those aspects of development that are specific to
the male. Much of the interesting male somatic development occurs in the tail, which in the adult contains
male-specific neurons, muscles, and epidermal cells that enable the male to copulate efficiently with
hermaphrodites. For the development of these tissues, some blast cells common to the two sexes initiate
male-specific cell lineages. In other cases, the same cells in the two sexes differentiate differently. The major male
mating structures form in dramatic morphogenetic events just before the last larval molt. Although the male somatic
gonad differs substantially in overall morphology from that of the hermaphrodite, the cell lineages that give rise to
the two somatic gonads are clear variants of each other.
In his chapter, Michael Herman focuses on cell fate specifications that occur only in hermaphrodites. Both
sexes make use of Hox genes and asymmetric distributions of the Wnt pathway transcription factor POP-1/Tcf for
patterning their anterior-posterior body axes, but these regulators are interpreted differently in the two sexes. The M
cell, for example, gives rise in hermaphrodites to (among other cell types) muscles needed in the mid-body region
for egg laying, whereas the M cell in males gives rise to muscles in the tail needed for copulation.
Paul Sternberg has written about a single hermaphrodite-specific organ, the vulva, which forms during larval
development and provides an opening between the uterus and the external environment. A remarkably detailed
description of the molecular events and individual cells involved in this process has emerged. Although the cell
lineage that gives rise to the vulva is invariant, it depends critically on three standard intercellular signaling
pathways: EGF-Ras-MAP kinase, LIN-12/Notch, and Wnt.
The descriptions of the differences between males and hermaphrodites naturally lead to the question of what
makes them different. David Zarkower explains in his chapter that the difference between male fate and
hermaphrodite fate for somatic cells is determined cell autonomously by a single master regulator, the transcription
factor TRA-1: hermaphrodite fate is specified when TRA-1 is active, and male fate is specified when TRA-1 is
inactive. This leads to two further questions, which Zarkower addresses: what makes TRA-1 active in
hermaphrodites and inactive in males, and what are the targets of TRA-1 action? The answer to the first question
involves a cell-nonautonomous, global sex determination pathway, which is fairly well understood and triggered by
an assessment of the ratio of the number of X chromosomes relative to the number of autosomes, the X:A ratio. The
second question presents a large gap in our understanding, since very few TRA-1 targets have so far been identified.
In their chapter, Ronald Ellis and Tim Schedl point out that sex determination in the germ line is not a simple
recapitulation of the regulation by TRA-1 that takes place in the soma. Although the same members of the global
sex determination pathway that act in the soma are required for sex determination in the germ line, the pathway
operates slightly differently, and TRA-1 is not the sole final arbiter of sexual fate. In addition, as one might expect,
certain germline-specific genes are needed to control germ cell fate.
Sex determination evolves rapidly, and Eric Haag's chapter is based on the idea that our detailed
understanding of sex determination in C. elegans makes it an attractive subject for studies in comparative biology.
Only two C. elegans genes are known to be related to genes with sex-specific roles in a wide range of animals:
mab-3 and mab-23 affect some male cell fates and belong to the DM domain transcription factor family, along with
the Drosophila gene doublesex and some vertebrate genes that also act sex-specifically. Because C. elegans sex
determination has otherwise evolved very rapidly, the most useful inter-species comparisons are with other
nematodes, as Haag indicates. Such studies should expand as the sequences of more nematode genomes become
No story of sex would be complete without a discussion of dosage compensation, and in the final chapter in
this section, Barbara Meyer describes how hermaphrodites assemble a protein dosage compensation complex
(DCC)—which is related to a chromosome condensin complex—all along their X chromosomes to dampen X gene
transcription just enough to make it equal to that found in X0 males. A functional DCC is not made in males owing
to the repressive effect of the gene xol-1, which is active in males and not in hermaphrodites. How xol-1 is activated
only in males is an interesting story told by Meyer involving X-linked repressors and autosomal activators that
enable xol-1 to respond appropriately to the X:A ratio. The status of xol-1 expression determines both the sex of the
animal—by affecting tra-1 expression via the global sex determination pathway—and whether or not a DCC will be