A genetic defect that makes mice stagger does its damage by leading developing nerve cells astray. The finding, reported in the current issue of Development, gives researchers new clues to how the brain organizes into distinct regions responsible for different tasks.
In mammalian embryos, billions of newborn nerve cells must move from a tube of primordial tissue to precise locations before developing into unique brain regions. What guides the migrating cells to their proper slots is unclear, but researchers recently discovered that a protein called netrin-1 can act like a magnet for nerve cells--attracting certain types to key locations, while repelling others. When migrating cells fail to sense the protein's presence, however, they get lost and end up in the wrong place, according to geneticists Susan Ackerman, Stefan Przyborski, and Barbara Knowles of the Jackson Laboratory in Bar Harbor, Maine.
In their study, the trio examined development of the cerebellum--the lower rear portion of the brain responsible for muscle coordination and posture--in normal mice and in a lurching breed known to have a mutated version of a gene called Unc5h3. To track the progress of migrating nerve cells, the researchers injected mice with radioactive chemicals that tagged both cells and netrin-l, then examined thin slices of brain tissue under the microscope. In normal mice, cells that form the cerebellum's surface stopped cold when they encountered netrin-1. In the mutant mice, however, the cells ignored the chemical boundary and kept going, eventually forming tangled knots of tissue in adjacent regions. The results suggest that the genetic mutation somehow disables a membrane protein that embryonic cells need to recognize netrin-1, says Ackerman. She believes a similar gene and mutation may play a role in ataxias, human coordination disorders.
"It is a really cool, lovely study that pulls together a lot of good work on how brain cells recognize boundaries," says Karl Herrup, a neurogeneticist at Case Western Reserve Medical School in Cleveland. He and Ackerman agree, however, that other proteins are probably involved in controlling cell movements. Says Herrup: "It's probably not the last set of protein interactions we will find that create boundaries."