Neurons Find Their Place In The Developing Nervous System With The Help Of A Sti

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Neurons Find Their Place In The Developing Nervous System With The

Help Of A Sticky Molecule

http://www.medicalnewstoday.com/medicalnews.php?newsid=42351

The brain, that exquisite network of billions of communicating cells,

starts to take form with the genesis of nerve cells. Most newborn

nerve cells, also called neurons, must travel from their birthplace

to the position they will occupy in the adult brain. Researchers at

the Salk Institute for Biological Studies have identified a molecule

expressed on the surface of certain migrating neurons that helps them

find their correct position along on the way.

Decreasing levels of that protein, an adhesion molecule called MDGA1,

prevents neurons that normally make this protein from assuming their

proper position, resulting in brain malformation, researchers report

in the April issue of the Journal of Neuroscience.

As Dennis D. M. O'Leary, Ph.D., senior author of the study and a

Professor in the Molecular Neurobiology Laboratory put it, " proper

neuronal positioning is essential for development of appropriate

wiring, which is in turn critical for establishing a normal,

functioning nervous system. "

Neurons migrate throughout the brain, but migration is particularly

important for development of part of the brain known as the cerebral

cortex. The cortex sits like a skullcap over the rest of the brain

and is responsible for sensory perception, higher-level reasoning,

and, in humans, language. In mammals, the largest and evolutionarily

newest part of the cortex, the neocortex, is recognized anatomically

by its six horizontal layers.

The neocortex develops outward from an underlying zone of cells. From

that zone, crawling neurons migrate radially out toward the surface

or " superficial " part of the developing cortex, giving rise to a

laminar structure. Neurons forming layers 2 and 3, the focus of the

current study, are born last and so must elbow their way through

cells lying in earlier formed layers to reach what will become the

outermost layers. Without MDGA1, these neurons begin to migrate but

get stuck before they reach their normal destination.

The MDGA1 gene was cloned and characterized first in rat by O'Leary

and two former postdoctoral fellows, E. Litwack, Ph.D. and

Matthias Gesemann, Ph.D. They showed that MDGA1 is a cell adhesion

molecule - a protein enabling cells to attach to other surfaces,

something that they must do either to move or sit still and elaborate

connections. They also showed that MDGA1 is expressed on

subpopulations of migrating neurons throughout the developing nervous

system, including layer 2/3 neurons in the neocortex, suggesting that

MDGA1 may actually be required for migration.

In the current study, O'Leary and Akihide Takeuchi, M.D., Ph.D., a

postdoctoral fellow and the study's first author, tested this

hypothesis. They first showed that layer 2/3 neurons make MDGA1

protein as they migrate to their destination. Then, utilizing a

cutting-edge molecular technique called RNA interference, the Salk

researchers silenced the MDGA1 gene. To do this, they painstakingly

performed in utero surgery on embryonic mice - injecting an

interfering RNA molecule into the lateral ventricle, a fluid-filled

space next to the neocortex. Application of an electrical current

forced the RNA into neural progenitor cells, and it was subsequently

inherited by their neuronal progeny that form layer 2/3 and blocked

their ability to make MDGA1 protein.

When Takeuchi and O'Leary examined the neocortex a few days later

when the mice were born, they discovered that nearly all neurons

containing the interfering RNA were stalled in aberrant deeper

locations, indicating that loss of MDGA1 protein had stymied their

attempt to travel the full distance to layer 2/3 and supporting the

original hypothesis. The goal now is to determine how MDGA1 controls

neuronal migration and what the long-term consequences are of its

loss.

Impaired function of neuronal adhesion molecules has been previously

linked to neurological defects in humans. A cell adhesion molecule

known as L1 has been shown to affect cell migration and positioning

in other parts of the nervous system. Numerous mutations in the human

L1 gene have been uncovered; individuals with these mutations often

show severe defects in neuronal positioning and connectivity, which

are clinically manifested in conditions such as hydrocephalus, mental

retardation and spastic paraplegia.

Whether mutations in MDGA1 lead to brain disorders remains to be

seen. " Much work needs to be done, and the appropriate tools need to

be developed to do this work, " said O'Leary, " but we feel that these

studies will eventually provide insight into neurological disorders

that have their basis in malpositioning of neurons. "

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The Salk Institute for Biological Studies in La Jolla, California is

an independent nonprofit organization dedicated to fundamental

discoveries in the life sciences, the improvement of human health,

and the training of future generations of researchers. Jonas Salk,

M.D., whose polio vaccine all but eradicated the crippling disease

poliomyelitis in 1955, opened the Institute in 1965 with a gift of

land from the City of San Diego and the financial support of the

March of Dimes.