Saturday, August 11, 2007

Development Primer: 3 Models of Sex Determination and Dosage Compensation, Part 2

Drosophila's sex chromosomes are perhaps more familiar-looking, in that it has an X and a Y chromosome, with XX animals being phenotypically female and XY animals being phenotypically male. As we'll see, however, the mechanisms are vastly different from what we see in humans and other mammals.

Sex determination and dosage compensation begin as they did in C. elegans with reading the X:A ratio. This time, however, the X-linked numerator factors (like daughterless and sisterless) drive Sxl (sex lethal) expression from a promoter that results in the code for a fully-active SXL protein (nomenclature note: italics are typically used for the name of the gene, capital letters are used for the corresponding protein). The A-linked denominator factors (like deadpan) bind to the numerator factors to inhibit their activity. Thus, if the fly has only one X chromosome, the denominator factors will titrate out the numerator factors, so Sxl only gets up and running in XX animals.

SXL a protein that alters RNA splicing. Most mRNA when it is first transcribed from DNA must first be processed within the nucleus before it is shipped out for protein translation. This processing includes removing introns, non-coding regions of DNA within a gene. Normal Sxl mRNA has a premature stop codon in its third intron; if the cell tries to make protein from this mRNA, it will stop translation short, resulting in a non-functioning protein. SXL protein is responsible for altering splicing to remove this intron so the cell can make more fully functional SXL.

Thus, SXL drives its own positive feedback loop. Both XX and XY animals express Sxl mRNA from the normal promoter. In XY animals, there isn't ever any SXL around to splice this mRNA, so no SXL is made. In XX animals, the numerator factors drive SXL expression at the beginning of development from a special promoter that doesn't require splicing, so there's enough SXL to kick-start splicing of the normal mRNA and keep generating more SXL long after the numerator factors stop working.

SXL is then responsible for proper splicing of tra to its active form, which in turn (in conjunction with tra-2) alters splicing of the transcription factor dsx, which causes differentiation to the female phenotype.

SXL also inhibits msls, a gene which otherwise would initiate dosage compensation by increasing expression from the male X. Note that in C. elegans, dosage compensation meant scaling down expression in the female, but in Drosophila, dosage compensation means scaling up expression in the male.

Drosophila summary:
Two sex chromosomes -- XX female, XY male. Numerator factors drive expression of fully-functional SXL in XX animal, kicking off SXL positive feedback loop. SXL activates pathway leading to female development. SXL inhibits msls pathway to dosage compensation. In the absence of SXL (i.e. in XY animals), msls drives increased expression from the single X chromosome.

(Cross-posted from Synapostasy)

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