Friday, August 10, 2007

Development Primer: 3 Models of Sex Determination and Dosage Compensation, Part 1

You're probably aware that a person's sex is typically determined by their combination of sex chromosomes. In humans, females have two X chromosomes, whereas males have an X and a Y. But how do you go from X and Y to boy and girl? And what does the cell have to do to compensate for the chromosome differences between the sexes?

Sex chromosomes pose two interesting questions in the study of development:
  1. Sex determination: How does the cell interpret the data from the sex chromosomes to result in phenotypic sex?
  2. 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?
The animal kingdom employs a number of different mechanisms for dealing with these two questions. Let's take a brief look at sex determination and dosage compensation in three model organisms: the nematode worm (Caenorabditis elegans), the fruit fly (Drosophila melanogaster), and the common mouse (Mus musculus).

C. elegans
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.

(Cross-posted from Synapostasy)

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