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http://www.eurekalert.org/pub_releases/2005-01/cp-dtg011405.php
Public release date: 19-Jan-2005
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Contact: Heidi Hardman
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Cell Press
Deciphering the genetic babel of brain cells
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Gene chips, or microarrays, have proven to be immensely important in
measuring the activity of thousands of genes at once in such cells as
cancer cells or immune cells. The use of these chips has given
scientists snapshots of gene activity that lead to better understanding
of the genetic machinery of the cells. This understanding has led to new
ways to kill cancers or to manipulate the immune system, for example.
Gene chips consist of vast arrays of thousands of specific genetic
segments spotted onto tiny chips. When gene extracts of cells are
applied to the chips, labeled with fluorescent indicators, genes from
the cell extracts attach to their complementary counterparts on the
chips. Measurements of the fluorescence of each spot give scientists an
indication of the activity of particular genes.
As vital as they are to studies of individual types of cells, gene chips
have proven to be less useful in efforts to understand the genetic
signatures of specific brain cells, because a myriad of subtly different
subtypes of brain cells are intertwined in brain tissue.
Now, however, researchers led by Jeffrey Macklis, Bradley Molyneaux, and
Paola Arlotta of the MGH-HMS Center for Nervous System Repair at Harvard
Medical School and Massachusetts General Hospital and Harvard Stem Cell
Institute have developed a way to distinguish particular brain cell
subtypes in tissue and to separate them for genetic analysis with
microarrays. Their technique will prove enormously helpful to
neuroscientists studying the development and function of the brain. For
example, it will enable researchers to genetically tag, manipulate, and
even knock out the function of specific subtypes of neurons to study
their function. Also, by comparing genetic profiles of cells in normal
and diseased brains, researchers can gain invaluable clues to the
origins of neurological disorders.
In their technique, the scientists first labeled a specific brain cell
in living brain tissue using fluorescent microspheres. They then used
microdissection, biochemical methods, and fluorescence-activated cell
sorting to separate out the particular brain cell subtype for genetic
analysis using DNA microarrays. Such cell sorting isolates those cells
that have absorbed the fluorescent microspheres.
In their paper, the scientists report using their new technique to
unravel the genes that are active in corticospinal motor neurons (CSMN),
which connect the cortex and spinal cord and carry the signals that
operate muscles. These neurons are important because their degeneration
contributes critically to amyotrophic lateral sclerosis (Lou Gehrig's
disease) and to the loss of muscle function in spinal cord injury.
Better understanding of the genes that control the development of these
neurons could aid in the development of treatments for these disorders.
In their experiments, the scientists isolated the neurons and analyzed
the genes that were active in CSMNs during stages of embryonic
development in mice. They compared these active genes with those of two
other closely related subtypes of such cortical neurons to discover
specific genes that are likely critical to CSMN development.
To demonstrate that their technique had, indeed, identified functionally
important genes, they knocked out one of the genes, called Ctip2, in
mice. The resulting animal had defects in the connections between the
cortex and spinal cord that showed that the gene was critical for CSMN
development.
"The data here support the idea that a precise molecular classification
of distinct classes of projection neurons is possible and provide a
foundation for increasingly sophisticated analysis of stage-specific
genes controlling corticospinal motor neuron development," concluded the
scientists.
Paola Arlotta, Bradley J. Molyneaux, Jinhui Chen, Jun Inoue, Ryo
Kominami, and Jeffrey D. Macklis: "Neuronal Subtype-Specific Genes that
Control Corticospinal Motor Neuron Development In Vivo"
The other members of the research team included Jinhui Chen of the
MGH-HMS Center for Nervous System Repair at Harvard Medical School and
Massachusetts General Hospital and the Harvard Stem Cell Institute
[presently at the Spinal Cord and Brain Injury Research Center of
University of Kentucky]; and Jun Inoue and Ryo Kominami of the Graduate
School of Medical and Dental Sciences at Niigata University. This work
was partially supported by grants from the NIH, Christopher Reeve
Paralysis Foundation, and ALS Association (to J.D.M.). P.A. was
supported by a Wills Foundation Postdoctoral Fellowship. B.J.M. was
supported by the Harvard M.S.T.P..
###
The context and implications of this work are discussed in a Preview by
Joseph D. Dougherty and Daniel H. Geschwind.
Publishing in Neuron, Volume 45, Number 2, January 20, 2005, pages
207-221.
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