FROM: FEAT DAILY NEWSLETTER
New Brain Development Gene Found
UCSD and Japanese Researchers Identify New Gene Involved In Development and
Function of Central Nervous System
http://www.eurekalert.org/releases/ucsd-uaj121500.html
A new gene directly involved in the migration of neurons to the
developing brain, and then in the ongoing function of the mature central
nervous system, has been identified and described by researchers from the
UCSD School of Medicine and the Shirakawa Institute of Animal Genetics in
Japan.
One of the mysteries of human development is how the vast number of
cells that are produced following fertilization of an egg are deployed to
create a human being. In the December 2000 issue of the journal Neuron, the
research team describes a protein called "NUDEL". NUDEL plays a critical
role as part of a transport complex that includes LIS1, a protein identified
in human patients with a severe neuronal migration defect. Together, these
proteins regulate the function of motor-molecules called dyneins that
transport cellular cargo such as organelles within the cell. This complex
helps newly formed brain cells migrate to specific regions of the embryonic
brain, ensuring proper development of the cerebral cortex, the center of
intellectual and cognitive function.
"The discovery of NUDEL helps us to fill in the details about how
neurons in the developing brain become wired. It provides some new
information about the way embryonic neuronal cells divide and travel to end
up in the right place at the right time in order to make the proper
connection in the adult brain," said Anthony Wynshaw-Boris, M.D., Ph.D.,
UCSD assistant professor of pediatrics and medicine and co-author of the
Neuron paper.
"As we increase our knowledge of neuron migration and the pathways by
which the proper connections are made, we might discover new approaches to
treating neurodegenerative diseases linked to breakdowns in this transport
system," added Shinji Hirotsune, M.D., Ph.D., of the Shirakawa Institute of
Animal Genetics. "We might also be able to develop innovative ways to repair
lesions using these pathways to deliver therapies directly to the diseased
part of the brain."
Human defects in neural migration leading to structural defects in the
brain have been linked to many disorders, such as epilepsy and
schizophrenia. One devastating example is lissencephaly, manifested by a
smooth brain surface and a disorganized cortex. Children with lissencephaly
suffer profound mental retardation, increasingly severe epilepsy, and early
death. Nearly 10 years ago scientists identified mutations in a gene called
LIS1 as one of the primary causes of lissencephaly. Subsequent research by
several laboratories has shown that this gene is essential for the
regulation of neuronal migration. When the gene is mutated in humans and
mice, the number of neurons in the brain appears to be reduced, with a
resulting profound defect in structure and organization of the brain.
However, the molecular and cellular functions underlying the role of LIS1 in
this process have not been well-defined.
In their Neuron paper, researchers from the laboratories of
Wynshaw-Boris and Hirotsune establish that the LIS1/NUDEL complex binds with
dynein motor-molecules. NUDEL is activated by the addition of a phosphate
group via an enzyme complex called CdK5/p35, which has been shown in
previous studies to be essential for neural migration. NUDEL is closely
linked to LIS1 on human chromosome 17 and mouse chromosome 11.
In studies of mice, the researchers show that once the brain is
formed, this transport complex moves into the neuronal axons, the long
tendrils that sprout from neurons to connect cells in the central nervous
system or the body's extremities. There, the NUDEL/LIS1/dynein complex may
be instrumental in transporting cellular material up and down the axon.
According to the researchers, the LIS1/NUDEL complex also appears to
play an important role in cell division and cell proliferation as well as in
cell survival. For example, this complex appears to play a role helping to
allocate the chromosome complement properly during cell division or mitosis
as the mother cell gives rise to two new cells. These are intriguing
findings that require further study, the scientists said.
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Source: FEAT Daily Newsletter
