Headless flies a brain-teaser

Hole-punching proteins and headless fruit flies could help decipher the development of the human brain.

Story Tom Bicknell

The Coral Warr Research Group

The Coral Warr Research Group’s Associate Professor Coral Warr,
Dr Travis Johnson and Dr Michelle Henstridge.

There’s an old saying that when all you have is a hammer, every problem looks like a nail. Sometimes, all you have is a hole-punch, and when you get down to the molecular level, a lot of problems appear to benefit from a little judicious perforation.

The membrane attack complex/perforin (MAPCF) family of pore-forming proteins are that cellular equivalent of a hole-punch, and in humans they play a key role in the immune system by driving holes through the cell membranes of pathogens to kill them.

These ‘membrane attack’ proteins appear to address a number of neurological and immunological problems, and have also been associated with embryonic development.

Until recently, the mechanism for that involvement had not been well understood. Findings from a collaboration of Monash University researchers is shedding light on how these hole-punches serve to both destroy and, in the case of embryonic development, create. Consequently, they could have significant implications for research into neurological diseases and cancer.

The research was a collaborative effort between Associate Professor Coral Warr in Monash University’s School of Biological Sciences, Professor James Whisstock in the Department of Biochemistry and Molecular Biology, Australian Research Council DECRA Fellow Dr Travis Johnson, and PhD student and now postdoctoral researcher Dr Michelle Henstridge.

Fruit flies are favoured in research because they’re an easy species with which to link individual genes to particular biological characteristics. One member of the MACPF protein family exists in fruit flies – the so-called ‘Torso-like’ protein.

fly

Related to perforin in humans, ‘Torso-like’ got its name for a very simple reason – female fruit flies without this protein produce embryos that are just a torso, lacking a head or tail. So, clearly the protein plays a role in the normal embryonic development in fruit flies. But what wasn’t previously understood was how.

“James came to us and said he had a member of this hole-punching protein family, but in a fruit fly, and he wanted to understand whether mechanistically it works the same as in humans,” says Professor Warr. “He had the protein background, and we had the flies and genetics background, and the ability to study gene function at a really sophisticated level, which is what the fruit flies enable.”

It sounds strange that a type of protein that is most often used to kill something is also actually used to make a developmental process.
Dr Travis Johnson

The collaborative team dived into the problem, and over the course of six years determined that the Torso-like protein was controlling the release of a specific growth factor that instructed embryonic cells to form a head and tail.

“It sounds strange that a type of protein that is most often used to kill something is also actually used to make a developmental process happen. It’s not trying to kill the embryo, obviously, so what is it doing there? That was the main question,” Dr Johnson says.

“We’re still working on the details, but what we’ve discovered is that it’s needed for this growth factor to actually be released from cells. When you take this protein away, the growth factor is stuck inside the cells, and you don’t get normal development happening.”

It’s a key finding – a previously undiscovered mechanism for controlling growth factors.

Brain development

The discovery also has significance for human biology. Other hole-punching relatives of the Torso-like protein that exist in humans are known to be associated with development of the brain. Understanding whether they regulate growth factors in humans in a similar way to fruit flies could inform new research into neurological disorders such as autism, schizophrenia and attention deficit hyperactivity disorder. Because of the relationship between malfunctioning growth factors and cancer, a broader understanding of growth-factor regulation could also have implications for research into that disease.

As for the next stage, there’s more to learn about how the Torso-like protein works, Dr Johnson says. “There’s still a lot for us to understand with this protein in fruit flies,” he explains. “It seems like this type of protein is really useful for the fly, they’re using it in a number of different places.”

The next step is to dig deeper into how the Torso-like protein causes the release of the growth factor. The team is exploring whether the protein uses its hole-punching capability to open cells to release the growth factor contained within, but in a manner that doesn’t kill the cell. To do this requires innovative microscopy and imaging approaches, which are being enabled with equipment and capability provided by the Australian Research Council Centre for Advanced Molecular Imaging, of which Professor Whisstock is director.

With a greater understanding, future studies are likely to move to vertebrate trials – a step closer to learning how these multi-purpose proteins work in humans, and what problems they may solve.

fly

FRUITFUL FLIES

It may be only 2.5 millimetres long, but Drosophila melanogaster can tell us a lot about how the human body works. The common fruit fly, or vinegar fly, shares about 75 per cent of our genes, and has served as a test-bed for genetic analysis for more than 100 years.

“A lot of really important discoveries in genetics and biomedical science are made using these flies, because a lot of their genes work exactly the same way as ours,” explains Associate Professor Coral Warr.

“I’ve studied various aspects of Drosophila my whole career. You get very addicted to the power of what you can do, particularly studying things at a cellular level.”

Professor Warr was attracted to fruit fly research because of its biomedical relevance – its ability to contribute to human health outcomes. That factor has been a drawcard, and the Coral Warr Research Group now operates out of the Monash School of Biological Sciences with 13 researchers and students specialising in fruit fly research. Five other research groups in the school also use fruit flies to study aspects of genetics, evolution and developmental biology, making it one of the world’s largest hubs for fruit fly research.

Because of the flies’ fast life cycle, small space requirements and low cost, the research is often at the forefront of genetic analysis.

“You find out things in the fly, because it’s easier, and then you go back to a mammal, a vertebrate, and you ask if these genes work in the same way in the mammal,” says Professor Warr. “But those are longer, more expensive experiments, so you can use your fly experiments to inform those.”