May 20, 2005
Gene Keeps Neural Cells on Correct Developmental Path
Embryonic stem cells with identical genomes grow into distinctive
tissues, such as heart, bone, and brain. At one time, scientists
believed the differences among cell types arose from various sets of
genes switched on inside developing cells. Then, studies showed that
adult neurons uniquely lack a protein that permanently turns off
neuronal genes in the rest of the body's cells.
Now, it turns out that precursor nerve cells contain that same
repressive protein after all. In fact, the protein directs the complex
network of genes that transforms an embryonic stem cell into a mature
nerve cell, say Howard Hughes Medical Institute (HHMI) researchers.
This new study, published in the May 20, 2005, issue of the journal
Cell, may be among the first to track a set of genes from stem
cell to differentiated neuron. It also reveals fundamental details of
how stem cells retain developmental plasticity.
"A single protein does it all," said Gail Mandel, HHMI investigator
at the State University of New York at Stony Brook. "It keeps the genes
totally off in non-neuronal tissues, such as skin, where you don't dare
express a neuronal gene. But it also allows the full elaboration of the
neuronal phenotype from the precursor cell."
Led by HHMI associate Nurit Ballas, a postdoctoral fellow in
Mandel's lab, the study may advance stem cell research aimed at
understanding repairing spinal cord injuries or replacing
malfunctioning brain cells in neurodegenerative diseases. It may also
provide insights into other diseases, such as small cell lung cancer,
which mistakenly make neuronal proteins, or neurological syndromes,
where neuronal proteins produced by cancers may trigger the immune
cells to attack the nervous system.
The study focuses on a protein called REST, which is short for
RE1-silencing transcription factor. It was independently discovered 10
years ago by Mandel's group and a second team led by HHMI investigator
David J. Anderson at Caltech. Mandel created the acronym to describe
how REST quiets the nerve genes. The protein is also known by the name
Anderson gave it, NRSF, for neuron-restrictive silencer factor.
Since then, they and others have found that REST locks down neuronal
genes in other cells by grabbing onto the DNA and cementing in other
molecules, an arrangement that stays intact as non-neuronal cells
differentiate into liver, muscle, and other tissues.
The new study reports that REST uses a different temporary off
mechanism to direct neuronal development. "This study shows that there
is more than one way to keep a REST-regulated gene repressed," said
Michael G. Rosenfeld, an HHMI investigator at University of California,
San Diego, who co-authored an accompanying commentary in Cell
with Victoria Lunyak, a research associate in his lab.
In contrast to the tight packaging of neural genes in other cells,
REST keeps the chromatin in embryonic stem and precursor neurons open
and poised for gene activity.
"REST keeps the brake on lightly until a trigger tells embryonic
stem cells it's time to make a neuron," Mandel said. The cell then
triggers the expression of an ensemble of genes that coordinates
nervous system development by removing REST in three distinct phases,
ending with shutting down the REST gene.
"The cell gets rid of all the excess protein, kicks it off the DNA,
then stomps on its head so it can't make RNA," Mandel said. "We can't
detect REST in the terminally differentiated neuron." But some
molecular partners of REST remain, perhaps fine-tuning gene expression
in mature neurons, she said.
REST seems to work globally, binding to the starting points of as
many as 1,000 genes at once. The gradual loss of REST in
differentiating neurons probably orchestrates a precise sequence of
genes sensitive to different levels of REST, Mandel speculates.
REST has been a difficult gene to study. Using knockout technology
— a popular technique for determining gene function — does not work
for REST because mice lacking the gene die before they are born.
Embryonic stem cells provided a way for Mandel to get around this
problem. Unexpectedly, they also revealed fundamental ways in which
stem cells remain plastic.
"This paper is like a whole story, beginning with the birth of a
neuron and ending with the death of REST," Mandel said.
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