Sex chromosomes pose two interesting questions in the study of development:
- Sex determination: How does the cell interpret the data from the sex chromosomes to result in phenotypic sex?
- Dosage compensation: The sex chromosomes carry many genes that aren't sex-specific; that is, both male and female cells need the products of those genes in approximately equal amounts. Without dosage compensation, a cell with two X chromosomes will produce twice as much of a given X-linked gene product as a cell with one X chromosome. How does the cell regulate sex chromosome expression so that cells with unequal sex chromosomes express sex-linked genes equally?
C. elegans is a tiny invertebrate worm with just one kind of sex chromosome: X. A normal worm with two X chromosomes (XX) is a hermaphrodite, producing both sperm and eggs and capable of self-fertilization. A normal worm with one X chromosome (XO) is a male; they're smaller and capable of mating with hermaphrodites.
The pathway leading to sex determination and dosage compensation is initiated by "reading" the X-to-autosome (X:A) ratio. (Autosomes are any chromosomes that aren't sex chromosomes.) In C. elegans, the first main gene in the signal transduction pathway is xol-1 (XO lethal 1, so named because mutations of the gene are lethal to animals with XO genotype). The autosomes express a number of genes, such as sea-1, that promote xol-1 expression; these are called denominator factors, since they show up on the bottom of the X:A ratio. Each X chromosome carries genes like sex-1 and fox-1 that inhibit xol-1 expression; these are called numerator factors. An XO cell doesn't produce enough numerator factors to "cancel out" the denominator factors, so xol-1 is "turned on." An XX cell has twice as much of each numerator factor, enough to "turn off" xol-1.
Xol-1 is the first in a series of several regulatory genes. Since the genes regulate each other, activity alternates down the chain. If xol-1 is on, then it turns off sdc-2, which means her-1 gets turned on, etc. Alternatively, if xol-1 is off, then sdc-2 gets to turn on, and that turns off her-1, etc. This pathway ultimately leads to expression of transcription factors (gene-regulating proteins) specific for either hermaphrodite or male differentiation.
Loss-of-function mutations of some of the genes in this pathway can cause "transformation" to the wrong sexual phenotype. For example, in XO animals her-1 is normally turned on, and we expect to get a male. But if we mutate her-1 so it can't perform its function, then the rest of the pathway downstream acts as if her-1 is off and we get a hermaphrodite phenotype. (Genes are often named according to the phenotype of the mutation that led to their discovery; thus, her-1 got its name for turning XO animals into hermaphrodites.)
So that's sex determination, but what about dosage compensation? It turns out that dosage compensation is activated by sdc-2. Dosage compensation in C. elegans acts by cutting expression of both X chromosomes in half in XX animals. That way, two X chromosomes at half-expression result in the same amount of product as one X chromosome at full expression. That's also why xol-1 mutations are lethal for XO animals; without xol-1 to regulate it, sdc-2 gets turned on when it shouldn't be. That in turn activates dosage compensation, and with only one X-chromosome at half its normal expression, the cell doesn't have enough X-linked gene product to survive.
C. elegans summary:
One sex chromosome -- XO males, XX hermaphrodites. X:A ratio read by X-linked inhibition of xol-1, affecting downstream chain of regulatory genes. Dosage compensation reduces expression from each X chromosome by half in XX animals.