The earth's outer shell consists of a dozen large tectonic plates and afew smaller ones. These discrete geologic masses move around andslip past each other, causing earthquakes as they go.

A newborn infant's skull also consists of several separate bony plates,designed to overlap in utero, and diminish the skull's diameter foreasier passage through the birth canal.

The largest soft spot in a baby's head, the fontanel, doesn't hardenover until the child is two years old.

At that same age, the brain beneath its skull winds up some of itsunfinished business: it completes the migration of young neurons totheir final destinations in the growing cortex and cerebellum.

These two adjacent events in fact have nothing intrinsic to do witheach other; they just underline that some aspects of fetal developmentgo on post-natally.

The little-known ways and means by which a neuron in the brainproceeds to its ultimate action station became a lot clearer today, withpublication of a paper in Science, dated April 19. Its title: "CNS[central nervous system] gene encoding astrotactin, which supportsneuronal migration along glial fibers."

Its senior author is neuroscientist Mary Hatten, who heads theneurobiology laboratory at Rockefeller Univer-sity in New York.

"Simply put," she told BioWorld Today, "the brain's architecture isestablished by a scaffold of glial cells that the neurons use toassemble the six different layers of the cortex. Another way oflooking at it," she went on, "is cars _ the neurons _ riding along theglial highway. The gene we discovered, and named astrotactin,encodes a protein, astrotactin, that corresponds to the wheels on thecars." It attaches to glial fibers in the developing brain, and travelsalong them.

Hatten pointed out that this protein "is the first molecule shown todirectly function in neuronal migration, and since all of the cells inthe cortical region of the brain _ cortex proper for thinking,hippocampus for memory, olfactory bulb for smell, and cerebellumfor sense of balance _ are assembled into layers by this mechanism;it's a fundamental piece of information."

Recipe For Brain-Cell Migration Gene, Protein

To make their discovery, she and her co-authors began by purifyingneuronal and glial cells from the cerebellum of mouse embryos."Then, over a long period of time, we carried out video microscopyto actually watch the neurons running on the glial monorail _ liketime-lapse photography. Next, we raised antibodies that blocked thatmigration, and cloned the proteins they inhibited."

Zeroing in on this protein, the Rockefeller team screened 39candidate molecules; number 14 displayed the migratory activity.

In humans, the cerebral cortex's six layers add up to a thickness ofseveral centimeters. Traversing that distance "is quite a journey,"Hatten observed, "because the little cells are only four microns insize. It's on the scale of walking from here to Denver."

The cells can migrate at speeds of 20 to 50 microns an hour, about1/1,000 of an inch, which, Hatten observed, is fast for a neuron.

Since submitting her paper to Science late last year, she and her teamhave been carrying out chromosomal localization of the astrotactingene, in collaboration with neurologist and cell biologist ElizabethRoss at the University of Minnesota in Minneapolis.

That work, nearly completed, Hatten said, "will show that the genemaps to a region of the human chromosome where defects in corticalformation are evident. The most clear-cut one is childhood epilepsy,which often turns out to be mainly a neuronal migration deficit."

Other such errors, she added, may include pediatric tumors,schizophrenia and degenerative diseases of old age.

Ross, who heads the laboratory of molecular neurobiology anddevelopment at Minnesota, told BioWorld Today that other suchchildhood diseases include microcephaly _ abnormally small brain _and cerebellar hypoplasia. "Magnetic resonance imaging," sheobserved, "shows that such developmental disorders can involve boththe cerebellum and the cerebral cortex."

Build-Up To Tackling Human Disorders

"Patients," she added, "are usually mentally retarded, and may ormay not have a seizure disorder."

Ross is screening DNA from the blood of several dozen affectedfamilies "to see whether we can find a mutation in the astrotactingene.

"We're still very much in the beginning stages," she emphasized,"being able to use this information to best advantage, for bothprevention and cure. Once we understand more about the function ofthe gene, there will be the hope of being able to ameliorate thesymptoms in an affected child."

Beyond that, "it may also teach us more about how the gene or theprotein may malfunction for pharmacological or environmentalreasons, so sporadic [non-inherited] cases can be prevented."

Hatten meanwhile "is pretty close to creating a knockout mouse thathas no astrotactin gene _ a null mutation _ to see what happens tothe formation of the cortex. We've prepared the mosaic animals, andare now assaying for germline transmission in our lab here atRockefeller." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.