Volker Hartenstein, University of California, Los Angeles

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 gut1. 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 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 cells 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.

The fly midgut and hindgut neatly separate processes that occur simultaneously within mammals

As cells move down the tube, they pass through zones of proliferation and then move into a region differentiation. This is quite similar to what is seen in the mammalian small intestine within areas that are known as crypts, which are found in the spaces between villi. The researchers found that 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 soluble 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 stem cells and hedgehog near the differentiated cells.

The crypt-villi system in mammals 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 layer. 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 within 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.”