ScienceWise - Jul/Aug 2007

Unravelling Ttyh1's Role: What a difference a gene makes

How a single gene can radically alter the way cells behave and the techniques used to probe gene action

Each of our cells carries a complete set of genes, but most of the time the majority of these genes are switched off. This is because there are many different cell types that make up our body and each cell type uses a different subset of genes in order to perform its function. For example, brain cells and liver cells are very different in appearance and behaviour, and employ different combinations of genes to achieve their specific functions.

Genetic manipulations can sometimes be used to understand how a gene functions. Essentially, a gene can be expressed in a specific cell type which is easy to culture, and often in cells where the gene normally switched off. Scientists can observe what happens by either turning a gene off, or over-expressing it. By comparing cells in which a gene of interest is expressed with normal cells of the same type (where the gene remains switched off), it’s possible to find clues about what the unknown gene does. The technique is called ectopic gene expression and Clay Matthews, a PhD student in the Molecular Genetics and Evolution group at the Research School of Biological Sciences, used this method to better understand a mammalian brain gene known as Ttyh1 (a human homologue of the fruit fly, Drosophila melanogaster, tweety gene).

As with all genes, the Ttyh1 DNA sequence exists in all of our cells but the Ttyh1 protein is only expressed in some brain cells. To determine the function of the gene, Mr Matthews modified the Ttyh1 gene so that it was fused to a small green fluorescent protein (GFP) and could be expressed in cultures of epithelial kidney cells. To observe what happened, he exposed the Ttyh1-GFP expressing cells to a specific wavelength of light which allowed the dynamics of the Ttyh1 protein to be observed (a control line of cells was also grown expressing just the GFP gene to ensure that any changes observed were not due to the GFP gene itself).

And what happened? The expression of this one gene had a dramatic effect on the shape and structure of the cell’s actin cytoskeleton. The cells began making contact with the underlying substrate and other nearby cells, and forming attachments via long Ttyh1-induced membrane protrusions. Normally the kidney cells are semi-rounded with a few angular regions – similar to the shape of Australia – but when Ttyh1 was expressed in these cells, long projections grew out from the cell surface. As these projections made contact with other cells or the underlying surface, they formed strong adhesive contacts and when cells moved forward by a process called cell migration, the projections remained bound to the underlying surfaces and surrounding cells. This led to the cell membrane being literally torn apart as the cell moved, and the consequent formation of deposits of the Ttyh1 protein remaining attached to the underlying surface and surrounding cells.

“This finding directed us to conduct research into the possible involvement of Ttyh1 in cell adhesion and cell migration,” says Clay Matthews. “Since that initial discovery we’ve been able to show that Ttyh1 is closely associated with other known cell adhesion molecules such as integrin, which can affect the cell shape by activating signaling cascades which eventually lead to the alteration of the cytoskeleton. The expression of Ttyh1-GFP in these cells led to a significant increase in the rate of cell migration”.

“Taken together with information from other experiments, these findings may show that the Ttyh1 protein is a new adhesion molecule in the mammalian brain. Adhesion molecules are important therapeutic targets as they are essential during processes such as development, wound healing and neuronal synapse formation.”

The results may also prove to be useful during the development of new technologies that require neurons (specialised brain cells) to attach to inorganic substrates such as in nano-scale printed circuit boards. Mr. Matthews is currently in discussions with researchers at the University of Adelaide and Nippon Telecom (Japan) about how to further develop these findings and other cell-substrate adhesion related projects.

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