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Study Reveals Patterns of Gene Activity in the Mouse Nervous System

The first published data from a government-funded project provide remarkable new insights into where specific genes are active in the mouse nervous system during development and adulthood. Information from this project will advance researchers' understanding of how particular genes function in the brain and spinal cord, leading to insights about how the nervous system works. It also may lead to new ways of preventing or treating disorders such as Parkinson's disease, Alzheimer's, psychiatric disorders, and drug addiction.

Data from the project, called the Gene Expression Nervous System Atlas, or GENSAT, are reported in the October 30, 2003, issue of Nature1. GENSAT is one of the first large-scale efforts to look at where specific genes are expressed, or translated into proteins, in the brain and spinal cord. The project builds on earlier efforts such as the Human Genome Project by helping investigators understand not only which genes are critical in the nervous system, but also what those genes do. All of the information from the project is publicly available to other researchers. The project is funded by the NIH's National Institute of Neurological Disorders and Stroke (NINDS).

"This paper presents the first fruits of a very ambitious project to map gene expression onto the anatomy of the mouse brain. We believe that this information will facilitate investigations in the function of the normal and diseased brain," says Story C. Landis, Ph.D., director of NINDS.

"With this project, we can generate extremely high-resolution information about gene expression. Looking at these genes at different points during development allows us to formulate hypotheses about gene function. It also directs us to previously unidentified genes that are interesting in the nervous system and allows us to visualize their expression in living tissue," says principal investigator Nathaniel Heintz, Ph.D., of The Rockefeller University in New York.

"We can see beautiful images of gene expression in living brain cells," says Mary E. Hatten, Ph.D., also of The Rockefeller University, who works with Dr. Heintz on the project. "This gives us a handle on many processes, such as where neurotransmitters are expressed in the brain." Among other possible benefits, this information could help investigators understand how neurological and psychiatric drugs work, she suggests.

The project, which began in September 2000, uses a two-stage process to identify potentially interesting genes and examine when and where they are expressed in developing mice. In the first stage, researchers led by Tom Curran, Ph.D., of St. Jude Children's Research Hospital in Memphis, use a technique called in situ hybridization to rapidly screen genes to see if, when, and where they are active in the mouse brain and spinal cord. In the second stage, which is the subject of the new report, Dr. Heintz and his colleagues use transgenic mice at three stages of development and in adulthood to study the genes that look most interesting. They create the transgenic mice by using normal cellular machinery in bacteria to generate artificial chromosomes that contain the gene of interest as well as a "reporter gene" that produces a fluorescent substance wherever the gene is active. They then insert these bacterial artificial chromosomes (BACs) into mouse egg cells. Mapping gene activity at several points as the egg cells develop into young mice reveals which cells express that gene and how they interact with other cells in the brain. The success of the project owes a great deal to the release of data from the Mouse Genome Project in 2002, Dr. Heintz says. "The release of that information has turned this into a very reproducible, highly successful enterprise."

The goal of GENSAT is to screen at least 600 genes per year using in situ hybridization, and to further analyze at least 250 genes per year using the BAC transgenic mice. An advisory committee assembled by the NINDS helps select the genes to be studied. "Having an advisory committee means this research is done with consensus from many parts of the neuroscience community," says Dr. Heintz. The committee members also help to evaluate ideas about how to use this research to advance neuroscience, he adds.

The data already generated by the project provide immediate opportunities for further investigation, the researchers say. For example, they have found that many of the genes studied to date are expressed in previously undescribed subsets of cells. Identifying these subsets of cells and what they do may lead investigators to a new understanding of how the nervous system works. An invaluable feature of the GENSAT project is that, in addition to identifying these novel cell populations, it also provides molecular tools and transgenic mice that can be used for further study. The report also shows how new information about several genes has led to insights about neuronal migration, interactions between axons and their target neurons, and other functions that may be relevant to understanding human development, behavior, and/or disease.

Data about each gene studied, including high-resolution images from the mouse nervous system at each stage of development, are available free of charge via a database at http://www.gensat.org. NINDS also has an agreement with the Mutant Mouse Regional Resource Centers, which are supported by the National Center for Research Resources (NCRR), to make transgenic mice generated during this project available to the research community. The first 100 mouse lines will be sent to these centers this year, and more will be added in the future. This will allow other researchers to obtain the mice much more economically and quickly than if they had to develop them in their own laboratories, Dr. Hatten says. The tools and mouse lines provided by this project will allow the neuroscience community to perform much more detailed studies of each gene, says Laura Mamounas, Ph.D., NINDS' project officer for the effort. GENSAT also may serve as a model for future gene expression projects, she adds.

The NINDS and the NCRR are components of the National Institutes of Health within the Department of Health and Human Services. The NINDS is the nation's primary supporter of biomedical research on the brain and nervous system.


1 Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB, Nowak NJ, Joyner A, Leblanc G, Hatten ME, Heintz N. "A gene expression atlas of the central nervous system based on bacterial artificial chromosomes." Nature, October 30, 2003, Vol. 425, pp. 917-925.

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