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Powerful New Tool For Studying Brain Development

Powerful New Tool For Studying Brain Development Scientists at St. Jude Children's Research Hospital have given investigators around the world free access to a powerful tool for studying brain development. The Internet-based tool, called the mouse Brain Gene Expression Map (BGEM), is one of the largest gene expression maps of an organ ever developed, according to the St. Jude researchers. They say the map will likely help scientists discover the genetic origins of brain cancers, which could speed development of novel drugs to treat them.

Scientists at St. Jude Children's Research Hospital have given investigators around the world free access to a powerful tool for studying brain development. The Internet-based tool, called the mouse Brain Gene Expression Map (BGEM), is one of the largest gene expression maps of an organ ever developed, according to the St. Jude researchers. (Image courtesy of St. Jude Children's Research Hospital)The continual updating and completion of the BGEM Web site will be crucial to scientists. More than half of the approximately 25,000 genes in the mouse are thought to be involved in the development and function of the nervous system, but scientists have determined the function of only 30 percent of them. Many brain disorders, such as tumors and some psychiatric diseases, are also believed to be caused by gene mutations that arise during development of this complex organ.

A report on the development and availability of the BGEM appears in the March 28 issue of PLoS Biology. The Web site is http://www.stjudebgem.org/

The similarity of the mouse and human brain make this map useful to researchers who study the development of the human brain and the origin of brain tumors from gene mutations, according to Tom Curran, Ph.D., co-chair of Developmental Neurobiology at St. Jude. "The BGEM represents a new strategy for exchanging information among researchers that will accelerate our understanding of the human nervous system," he said. "I foresee a time when researchers will be able to do certain studies to confirm hypotheses using a computer interface that links our data to many other kinds of gene information, without the need to go into a regular laboratory."

The BGEM is a growing, encyclopedic collection of tens of thousands of images as seen through a microscope. The images are obtained at distinct time points and show where and when specific genes are expressed at each of four developmental stages. Gene expression is visible because special tags called probes bind to messenger RNA (mRNA)--the decoded form of the gene--and release a signal that can be seen using a special microscope. Gene expression refers to the production of mRNA, which becomes the blueprint the cell uses to make the protein coded for by that gene.

The BGEM links these images with the most up-to-date information on those genes, such as their function, location on chromosomes and exact DNA sequence. The BGEM gathers this information through direct links to the scientific databases PubMed, LocusLink, Unigene and the Gene Ontology Consortium, which is housed at the National Center for Biotechnology Information in the National Library of Medicine. In turn, the BGEM images are used by the Gene Expression Nervous System Atlas (GENSAT), which seeks to document the expression of all genes in the nervous system. GENSAT is supported by the National Institute of Neurological Diseases and Stroke (NINDS), and a partnership of 14 institutes and centers of the National Institutes of Health (NIH), which have formed a consortium to accelerate breakthroughs in understanding the nervous system. St. Jude undertook the BGEM project under subcontract from Rockefeller University (New York) on behalf of NINDS.

"A researcher who discovers a previously unrecognized gene that is expressed during brain development can rapidly determine how it fits into the overall scheme of brain development," said Craig Brumwell, PhD, the GENSAT manager in St. Jude Developmental Neurobiology. "The BGEM helps researchers skip over much of the drudgery of digging up information from the literature or from other databases."

The BGEM already contains detailed information and images of the expression of hundreds of genes that play key roles directing brain development, controlling the expression of other genes, guiding protein production and transporting molecules within the cell.

A key part of the BGEM's success was the development at St. Jude of bioinformatics software that routinely searches scientific databases for new information on genes linked to brain development, said Perdeep Mehta, Ph.D., the group leader in bioinformatics at St. Jude's Hartwell Center for Bioinformatics and Biotechnology. Bioinformatics is the use of computers, software and other technologies to gather, organize, format and use large amounts of biological information. "Our ability to link images of gene expression patterns to information on those genes in other databases increases the value of each new gene discovery," Mehta said.

This integration of multiple research approaches and information provided by the BGEM was key to the success of a St. Jude study of the origin of human brain tumors in children. The team used a technique called microarray analysis to study gene expression patterns in samples of human brain tumors called ependymomas. By comparing the gene expression patterns in human ependymomas with those in the normal developing mouse nervous system provided by the BGEM, the St. Jude investigators demonstrated that specific brain cells, called radial glial cells, likely gave rise to ependymomas.

"Our demonstration that identical-looking ependymomas that arise in different regions of the central nervous system are distinct diseases because they arise from different stem cells is an important insight," said Richard Gilbertson, M.D., Ph.D., the senior author of a report on this work that appeared in the October 2005 issue of Cancer Cell. "This suggests that treatments should be designed to kill the underlying cancer stem cell population. If you kill only the cells making up the bulk of the tumor, the disease will likely return, because you haven't eliminated the source of the tumor.

Further, our comparative analysis of malignant and normal developing tissues provides a new method of mapping stem cells of solid tumors. The contribution of the BGEM was invaluable to our work and likely will lead to important discoveries that will improve the treatment of brain cancer."

Other authors of this study include Susan Magdaleno (formerly with St. Jude Developmental Neurobiology; now with Ambion Inc., Austin, Texas); Paul Jensen (Harvard University, Boston); Andrew Asbury and Christopher Eden (both with St. Jude Developmental Neurobiology); Anna Seal, Karen Lehman, Tony Cheung, Tommie Cornelius and Diana Batten (formerly with St. Jude Developmental Neurobiology); Dennis Rice (formerly with St. Jude Developmental Neurobiology; now with Lexicon Genetics, The Woodlands, Texas); and Nilesh Dosooye (formerly at St. Jude's Hartwell Center for Bioinformatics and Biotechnology; now at Yahoo.com); and Sundeep Shakya (St. Jude's Hartwell Center).

This work was funded in part by NIH and NINDS GENSAT.

St. Jude Children's Research Hospital St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org .