Here’s an account of a recent Nature paper. This will be an official article on Nature Reports on July 24.
Stretched out to its full length, your small intestine would be about five metres taller than you. It would take some 7,000 fruit flies, each standing on top of another, to reach that height.
That image is not quite as odd as it seems. Work led by Volker Hartenstein at the University of California, Los Angeles, shows that cell development within the hindgut of Drosophila is strikingly similar to that within the crypts and villi of the mammalian gut. Indeed, even the movement and differentiation of stem cells in the fly hindgut seem to mirror those seen within villi, the finger-like projections lining the small intestine. Thus, Drosophila could become a powerful model organism for studying this stem cell system.
Hartenstein decided to study the fruitfly hindgut through a mixture of logic and luck. In the 1980s he began researching neural development in Drosophila using classical genetics. When he found that one of the genes he was studying was profoundly important in blood development, he began work in that system as well. Fly blood is a clear liquid dominated by monocyte-like cells, but the early steps of blood development have multiple parallels to humans, says Hartenstein. However, studying the blood stem cell system can also be difficult: as flies reach adulthood, the sites where blood proliferates in larvae disappear. In fact, flies are so short lived that blood cells may not proliferate at all in adults.
Hartenstein had decided to hunt out another stem cell system when Shigeo Takashima, who had experience in gut development, joined Hartenstein’s lab as a postdoc. Stem cells in the fly’s midgut had recently been discovered and had garnered a great deal of attention, so Hartenstein and Takashima began looking in the hindgut, which is the section that follows the midgut.
They quickly found striking differences between cell proliferation in the midgut and in the hindgut. Each stem cell division in the midgut results in another stem cell and one other cell that differentiates without dividing again. And stem cells are scattered throughout the region. Conversely, in the hindgut, stem cell progeny proliferate and are also confined to a narrow ring at the beginning of the tube.
As cells move down the tube, they pass through zones of proliferation and then move into a region differentiation. This behaviour is quite similar to that is seen in the mammalian small intestine in the infolded areas known as crypts, which are found between villi and contain the stem cells of the gut epithelium. Not only is the arrangement of cells similar, but so are the signals governing self-renewal, proliferation and differentiation. In mammalian crypts, stem cells must be exposed to a secreted protein called Wnt to proliferate or self-renew. Another protein, called Sonic hedgehog, antagonizes the Wnt signal, causing the cells to differentiate. Hartenstein found that the fly homologs — Wingless and Hedgehog — likely carry out the same functions, and that they are produced at opposite ends of the fly hindgut proliferation zone: Wingless in the region of the stem cells and Hedgehog near the differentiating cells.
The crypt-villi system is more complicated than a fly hindgut. In the villi, stem cells can differentiate into several cell types. In the hindgut, the cells eventually become part of a smooth, homogenous tube. But Hartenstein says that this simplicity could be a boon. Indeed, he thinks that the fly midgut and hindgut neatly separate processes that occur simultaneously in mammals. Experiments in Drosophila could also be used to explore how these niches are established during development. The midgut could help researchers figure out how a single cell type can give rise to different fates; the hindgut could illuminate the tight architecture of the niche in the hind gut, with its zones of proliferating and differentiating cells.
In larger animals, it can be difficult to trace where signals are coming from and which cells are most important, Hartenstein says. “In Drosophila that’s more straightforward; you can really study questions at the single-cell level.”
1. Takashima, S. et al. The behaviour of Drosophila adult hindgut stem cells is controlled by Wnt and Hh signalling. Nature advance online publication, doi:10.1038/nature07156 (16 July 2008).
Monya Baker is editor of Nature Reports Stem Cells.