Volume 8, Number 16 May 4, 2001

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Study of ‘homeobox’ gene offers exciting prospects

This past journal illustration by T.C. Kaufman and colleagues from Indiana University shows how when the ‘pb’ (proboscipedia) gene in the fruit fly – the fruit fly’s homologue or equivalent gene to the Hoxa2 gene being studied by Nazarali, Doucette and Wolf – is mutated, it causes a transformation of the fruit fly’s mouth parts (slide A) into legs (slide B).
From left, Prof. Adil Nazarali, grad student Louise Wolf, and Prof. Ron Doucette take a break in the U of S lab where they are looking into the role of homeobox genes in vertebrate development.

By Susan Echlin
SPARK Writer

A gene that can change fruit fly antennae into legs may one day help prevent drug-related birth defects and ease the suffering of multiple sclerosis patients.

Assoc. Prof. Adil Nazarali, from the College of Pharmacy and Nutrition, in collaboration with Prof. Ron Doucette of the College of Medicine, is looking into the role of homeobox genes in vertebrate development. Homeobox genes are master genes that, while small in number, take on the important role of instructing all the other genes how to work together to create a viable organism.

An article co-authored by graduate student Louise Wolf, Doucette and Nazarali on the potential role of homeobox genes in forebrain development was recently published in the peer-reviewed journal NeuroReport.

These master genes have profound developmental effects on an organism, and mutations of the homeobox gene can have great effect on the development of the embryo.

"The ultimate question is what are the downstream targets of these master regulator genes and how are these genes orchestrated to give rise to a three-dimensional organism," says Nazarali.

The first homeobox gene was discovered in the early 1980s in fruit flies. An isolated homeobox gene, now known as Antennapedia, was discovered when a particular mutation in that gene resulted in an anatomically normal leg developing in the spot where an antenna should be. Since then, homeobox genes have been widely found to direct patterns in the embryos of all animal species.

Through funding from the Natural Science and Engineering Research Council (NSERC), Nazarali’s research program is studying the functions of homeobox genes and how they target certain proteins and genes to affect embryonic development. This research is also leading to a larger understanding of how master genes regulate development of the brain and spinal cord in vertebrates.

Nazarali is interested in a specific homeobox gene, Hoxa2, which he cloned while working with Nobel Prize winner Marshall Nirenberg at the National Institutes of Health in Bethesda, Md. In collaboration with neuroscientist Doucette and the rest of the team, Nazarali is now looking at how mutations of the Hoxa2 gene affect the embryonic development of mice.

"Mice were chosen for this research as they not only share almost 99 per cent of our genes, but their genetic makeup is also well characterized for study," he said.

The team has the only colony of Hoxa2 mutant transgenic mice in Canada. These mice exhibit a number of defects including the development of an extra set of inner ear bones, enlarged cerebellum, and a cleft palate. The mice invariably die within 24 hours of birth.

Of particular interest is the similarity between birth defects resulting from Hoxa2 mutations and those caused by certain drugs such as anti-convulsants for use in epilepsy.

This observation has led to further work studying the mechanism by which certain drugs may alter homeobox genes in developing organisms.

The Canadian Institutes of Health Research (CIHR) and the MS Society of Canada have just funded Nazarali and Doucette on a related study into how Hoxa2 affects the production of myelin, the sheath that covers nerve fibres. Patients with multiple sclerosis undergo a loss of this sheath, or demyelination. The team hopes to discover why patients with MS undergo demyelination and whether that process can be reversed, perhaps through drug therapy.

Nazarali has five graduate students working with him and he strongly emphasizes the contribution of graduate students to the team.

"Graduate students are absolutely integral to this research program," he says. "Without their input and hard work, it would be difficult to get the work done."


For more information, contact communications.office@usask.ca


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