Gene keeps neural cells on correct developmental path

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Gene keeps neural cells on correct developmental path

19 May 2005 Medical News Today

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 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 J. at Caltech. Mandel created the acronym

to describe how REST quiets the nerve genes. The protein is also

known by the name 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 G. Rosenfeld, an HHMI investigator at University of

California, San Diego, who co-authored an accompanying commentary in

Cell with 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.

Medical Institute

http://www.hhmi.org