Scientists Discover New Gene Essential
For The Development
Of Normal Brain Connections Resulting From Sensory Input
By Sherry Seethaler
the University of California, San Diego and the Johns Hopkins
University have discovered a gene that plays a key role in initiating
changes in the brain in response to sensory experience, a finding
that may provide insight into certain types of learning disorders.
After birth, learning
and experience change the architecture of the brain dramatically.
The structure of individual neurons, or nerve cells, changes
during learning to accommodate new connections between neurons.
Neuroscientists believe these structural changes are initiated
when neurons are activated, causing calcium ions to flow into
cells and alter the activity of genes.
In a paper featured
on the cover of the January 9th issue of the journal Science,
biologists at UCSD and the Johns Hopkins University medical
school report the discovery of the first gene, CREST, known
to mediate these changes in the structure of neurons in response
the gene CREST using a new method we developed to identify genes
that are switched on in the presence of calcium,” says
Anirvan Ghosh, a professor of biology at UCSD who headed the
study. “The brains of mice lacking CREST appear normal
at birth, but do not develop normally in response to sensory
experience after birth. This parallels some learning disorders
in humans where the child appears normal initially, but by the
age of two or three years it becomes clear that there are failures
in the acquisition of new knowledge.”
of neurons from normal mice (left) and from mice lacking
CREST gene (right) Credit: Anirvan Ghosh
Neurons from normal
mice develop a highly branched tree-like structure. In fact,
much of the growth of the brain that occurs soon after birth
is the development and branching of dendrites—the part
of a nerve cell that receives input from other neurons. Thus,
this branching allows neurons to form many different synapses,
or connections, with many other neurons, permitting much cross
talk between them. Neurons taken from mice lacking the CREST
gene are more linear, like a plant shoot.
In addition, when individual
neurons kept alive in a Petri dish are stimulated with calcium
ions, they respond by developing highly branched dendrites,
but neurons taken from mice lacking CREST fail to branch in
response to calcium.
“CREST is the
first example of a transcription factor—a protein that
turns genes on and off—that appears to be specifically
required for the development of brain neurons after birth,"
explains Ghosh, who conducted the study at his former laboratory
at Johns Hopkins.
His new laboratory
at UCSD is currently working to determine what gene is targeted
by CREST. Ghosh suspects the CREST gene might be turning on
the production of chemicals called growth factors, for the stimulatory
effect they have on cell development.
The CREST protein produced
by that gene is made in several regions of the brain immediately
after birth. In adults, the protein is produced in a region
of the brain known as the hippocampus, which plays an important
role in learning and memory. Because of this, Ghosh suspects
that CREST may be necessary for the storage of new memories
and the ability to learn. His laboratory is currently developing
mice in which CREST expression is normal throughout most of
development, so the brain develops normally, but then shuts
off in the hippocampus when the mice reach adulthood. In this
way, the researchers can test the specific role of CREST in
learning and memory in adults.
have CREST, and the CREST gene sequence is highly similar between
mice and humans,” says Ghosh. “If it turns out that
CREST plays a role in learning and memory in the mouse, then
it is very likely it also plays a similar role in humans.”
The other researchers
involved in the study are Hiroyuki Aizawa, Shu-Ching Hu, Kathryn
Bobb, Karthik Balakriashnan, Inga Gurevich and Mitra Cowan.
The study was supported by the National Institutes of Health,
the March of Dimes Birth Defects Foundation, the Klingenstein
Foundation, Merck and the Uehara Memorial Foundation.
Media Contact: Sherry Seethaler
Ghosh (858) 822-4142