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Arthur leads Journal Club on 3-21-16, discussing a recent paper in Nature by Hudry et al.

Lesson: Don’t mix data containing males and females

Cells have sexual identity. D. melanogaster determine cell’s sexual identity based on the sex chromosome to autosome ratio. Cells with 2X:2A ratio are females, while cells with 1X:2A ratio are males. The gene sxl is only expressed in XX cells. Sxl in XX cells are responsible for sex-specific splicing of tra non-coding mRNA into a protein-coding isoform.

Hudry et al. reported via RNAseq, clear differences in gene level and isoform expression between adult male vs female intestines (eg. female guts are enriched in cell cycle genes etc). They showed that activity of the intestinal stem cell, both at homeostatic and regenerative conditions, are sexually dimorphic. Female ISCs are more active; they undergo arguably shorter cell cycles, than male ISCs. Hudry et al. attributed these differences to the sex-specific expression of Sxl, Tra and their targets in XX ISCs. Genetic manipulations to masculinize XX ISC or feminize XY ISCs, abrogated the sexual dimorphism. Again, using RNAseq, they identified downstream targets of tra, that were shown to be responsible for the intestinal sexual dimorphism. Manipulating the levels of these targets in either XX or XY cells, abolished the sexually dimorphic intestinal response.

Interestingly, the sexual dimorphism in the intestine affects physiology of the fly. Female flies with masculinized ISCs were comparably less fecund. In addition, like normal female flies, males flies with feminized ISCs succumb to genetically induced tumor (via knocking down Notch, or APC tumor suppressor pathway). It won’t be surprising that  intestinal sexual dimorphism should also affect the animals’ lifespan. Regan et al. reported that dietary restrictions benefits female more than male flies  ie. extends female lifespan more than the males.  Using genetic manipulations to make transgendered intestines. they feminized male guts, and conferred substantial increases in male lifespan upon dietary restriction. 

Taken together, these findings indicated that sexual determination is active and reversible in the fly ISCs. Importantly, sexual dimorphism influences animal physiology and disease-susceptibility.

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