N.Y. Times
September 9, 1997
First Gene for Social Behavior Identified in Whiskery Mice
By NICHOLAS WADE
In a stroke of inspired good fortune, biologists have found a gene that
turns out to exert profound effects on the social behavior of mice. This
is apparently the first gene to be isolated that affects social behavior
in mammals, the authors and others say, and it promises to shed light on
important disorders of human social behavior like schizophrenia and
autism.
Mice that lack the gene look normal and achieve normal grades on tests of
learning and memory. But their social behavior is subtly different. They
interact with each other less often than do standard mice. They huddle
together less, they do not fluff up suitable beds from their nesting
material, and they fail to trim one another's whiskers properly. The
inattention to barbering is a sign that they do not form the social
hierarchy customary among this strain of laboratory mice, in which the
dominant mouse trims the whiskers and facial hair of its social inferiors.
"I think this is the first gene to be described that controls social
interactions," said Dr. Anthony Wynshaw-Boris, a clinical geneticist at
the National Human Genome Research Institute and chief author of the
study.
Dr. Richard S. Nowakowski, a neurobiologist at the University of Medicine
and Dentistry of New Jersey, said the new finding marked the first time a
gene had been found to affect behavior in a mammal. "It is a great leap
forward in terms of our thinking about limbic system diseases," he said,
referring to schizophrenia and autism, because it "provides molecular
clues as to what is going on in these deficits."
The finding was made by means of knock-out mice, animals in which a single
gene has been removed or knocked out by genetic engineering. Dr.
Wynshaw-Boris and his colleagues decided to knock out the mouse version of
a gene discovered in fruit flies, a standard laboratory organism. The gene
is called "disheveled" because flies with a mutant version die or develop
with disarranged chest hairs and other afflictions.
The disheveled gene is part of a cell-to-cell signaling pathway, one so
important that it is found in mice and humans, too, despite the millions
of years of evolution that separate mammals from fruit flies. Scanning
mouse DNA for genes of similar structure to the fly gene, biologists have
found three versions of the gene, known as disheveled 1, 2 and 3.
To learn the gene's role in mice, Dr. Wynshaw-Boris decided to knock out
disheveled-1; he expected its absence to make the mice develop abnormally,
as do fruit flies that lack the gene. He was surprised to find that the
mice looked normal when they grew up. But after colleagues noticed the
unusually bushy whiskers of the knock-out mice, a battery of behavioral
changes came to light.
One of the most interesting is an inability to screen out extraneous noise
and focus on a single stimulus. This symptom, as well as abnormal social
behavior, are found in several human psychiatric disorders, like
schizophrenia and Tourette's syndrome. Abnormal social behavior is also a
feature of autism.
Schizophrenia is thought to have a strong genetic as well as environmental
component because the disease is more common than usual among a patient's
relatives. From analysis of family pedigrees, epidemiologists have
identified several sites on human chromosomes where genes predisposing
toward schizophrenia are thought to lie.
Dr. Anne E. Pulver, an epidemiologist who studies schizophrenia at the
Johns Hopkins University School of Medicine, said the finding was "really
fascinating and needs to be followed up." Although the finding has no
immediate relevance to patients, she said, the discovery of genes that
predispose toward schizophrenia would help pharmaceutical companies
develop drugs, and the mice might be helpful in testing them.
None of the present candidate regions on human chromosomes for genes
predisposing toward schizophrenia includes the sites of the human versions
of the disheveled genes. But there are probably several more such regions
to be found, so the human disheveled genes are not excluded as possible
causes of the disease, Dr. Pulver said.
While there are obvious pitfalls in comparing humans with mice, especially
in terms of behavior, the two species share a surprising amount in common
at the level of their genes.
Whatever its relevance to psychiatry, the new finding has fished out two
ends of a very interesting chain, with the disheveled gene at one end and
the array of complex behaviors at the other. The connecting links are at
present unknown. "We have no idea what the pathways are that go from the
beginning to the end," Wynshaw-Boris said, "or what goes on between the
mutation and the social interactions."
The function of the disheveled gene is unknown, other than that its
product is one of the first members of an essential communication chain in
which a cell signals its neighbor. In the fruit fly this communication
system, called the wingless pathway, is used to organize the cells of the
developing embryo so that each segment of the fly knows its head from its
tail.
When a good system has evolved, nature often adapts it to other uses, and
it may be that the wingless pathway has been assigned a role in the adult
mammalian brain as well as in development. In the mouse the three
disheveled genes are known to be switched on during development of the
embryo, and disheveled-1 is also active in the adult mouse, particularly
in two regions of the brain known as the cerebellum and hippocampus.
In mice lacking the disheveled-1 gene, the wingless pathway is presumably
at risk of complete shutdown since a critical component is missing.
Wynshaw-Boris suggests that in his knock-out mice, the disheveled-2 and
disheveled-3 genes can compensate for the lack of disheveled-1 during
development, which is why the mice appear normal but cannot remedy the
lack of disheveled-1 in the brain.
Wynshaw-Boris said he had not yet shown his mice to psychiatrists, who
might confirm parallels with disordered patients, nor had he given them
antipsychotic drugs to see if their symptoms would abate.