Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCSD Researchers Describe Cell Activity Leading to Disruption of Neuron Migration

22.01.2004


An interaction between two brain proteins that leads to abnormal brain development has been identified by researchers at the University of California, San Diego (UCSD) School of Medicine in a study published in the January 22, 2004 issue of the journal Neuron.



The studies in mice, conducted in the lab of Joseph G. Gleeson, M.D., UCSD assistant professor of neurosciences, combines work in both humans and mice to identify a protein kinase called Cdk5 as the “off” switch for a crucial neuronal migration protein called doublecortin. When Cdk5 adds a phosphate molecule to doublecortin, the doublecortin is inactivated and neuronal migration is arrested.

In the normal brain, neurons are born deep within fluid filled cavities of the brain during the third and fourth month of gestation. Then, they must migrate hundreds of cell-body distances to reach their proper position within the six-layered cortex. When this migration is defective and neurons are stopped short of their destination, there is an absence of the normal grooves and ridges that characterize the brain in higher mammals.


A severe brain disorder in newborns, called lissencephaly, or “smooth brain,” is a result of abnormal neuronal migration where only four, instead of six layers of cortex are formed. Those children who survive the mutation suffer from profound mental retardation, epilepsy and cerebral palsy. Gleeson and colleagues previously showed that mutations in the doublecortin gene account for approximately 20 percent of the cases of lissencephaly in humans.

The study concluded that Cdk5 phosphorylation and inactivation of doublecortin takes place normally in the developing brain, but that it is balanced by reactivation of doublecortin by an as-yet-unidentified “on” switch. It appears that the regulation of this phosphorylation is critical for migration, and that both inactivation and reactivation are required for the normal functioning of the protein. Gleeson’s laboratory is currently searching for the signals that serve as the “on” switch to reactivate doublecortin.

“Neuron migration is poorly understood by scientists,” he noted. “With the discovery of Cdk5 as a factor that regulates doublecortin, we are learning more about this vital developmental process. Eventually, discoveries such as this will contribute to therapies to prevent abnormal brain development.”

In back-to-back published articles in 1998, Gleeson and a team led by Christopher A. Walsh at Harvard*, and a group of French scientists co-discovered doublecortin as one of the genes that causes lissencephaly when it is mutated. Further studies in 1999 by Gleeson and colleagues determined that doublecortin directly binds to microtubules, part of the cellular cytoskeleton that acts like a railroad track for the contents of neurons that move in the brain. However, researchers still didn’t know how doublecortin worked or what regulated its function.

In the current study, the Gleeson team used sophisticated molecular technology to determine that Cdk5 interacts with doublecortin to add a phosphate molecule to a precise site on the protein. Next, the team inactivated Cdk5 in one group of neurons, thus preventing its phosphorylation of doublecortin. When these neurons, or neurons containing mutant doublecortin, were pitted in a race with normal neurons, they stopped short of their goal, indicating that this regulation by Cdk5 was critical for the function of doublecortin on the cells’ ability to move.

In the January 22 issue of Neuron is commentary about the Gleeson discovery by Joseph Lo Turco, Ph.D., University of Connecticut, who notes that doublecortin may “sit at the center of a general cellular program of morphological change engaged as neurons migrate through developing neocortex.”

Additional authors of the UCSD paper included first author Teruyuki Tanaka, M.D., UCSD Department of Neurosciences; Finley F. Serneo, M.D., UCSD Department of Neurosciences; Huang-Chun Tseng, Ph.D., and Li-Huei Tsai, Ph.D., Department of Pathology, Harvard Medical School and the Howard Hughes Medical Institute; and Ashok B. Kulkarni, Ph.D., Functional Genomics Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health.

The study was funded by the Epilepsy Foundation of America; the Searle, Merck and Klingenstein Foundations; and the National Institute of Neurological Diseases and Stroke.

##

*Gleeson et al, Cell, 92(1): 63-72 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=9489700&dopt=Abstract

News Media Contact:
Sue Pondrom
619-543-6163

Sue Pondrom | UCSD
Further information:
http://health.ucsd.edu/news/2004/01_21_Gleeson.html
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=9489700&dopt=Abstract

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>