The fine art of brain development  pg. 3

They also appear to be very flexible, he notes. “We’re finding that the oligodendrocyte is very plastic … We’re beginning to get the sense that there are different kinds of oligodendrocytes. There are certain mutations that result in the absence of one kind of oligodendrocyte, but these may be rapidly replaced by another kind.”

After moving his lab to the University of Colorado Denver School of Medicine this summer, Appel plans to continue his search for genes that guide the developmental stages of oligodendrocyte progenitor cells (OPCs)—the immature cells that develop into mature oligodendrocytes—and the genes that determine their unusual behaviors.

To find them, Appel’s team uses a traditional genetics approach—causing random mutations in zebrafish embryos and screening these “mutants” to find ones with disrupted oligodendrocyte development.

He hopes that these mutants will point to genes that influence their specification (whether they go on to become an oligodendrocyte or another type of neuron), how fast they divide, and how they recognize and insulate their “target” axon and not other axons.

“We’re picking up mutations that affect all of those things,” he says. One mutant, called pescadillo, or “little fish,” produces an excess of OPCs, perhaps due to a genetic defect that causes their multipotent precursor cells (even more primitive cells than the OPCs that can produce oligodendrocytes or motor neurons) to continually divide. Another mutant, which Appel has aptly dubbed Peter Pan, has OPCs that “never grow up” —they don’t mature into myelinating cells.

His lab will try to identify the genes affected in these mutants—not an easy task, to be sure. But he says, “It’s going to be a lot of fun to work through.”

Using another approach, a screen for chemicals that disrupt oligodendrocyte development, Appel has found compounds that cause an excess formation of oligodendrocyte lineage cells.

“This was far beyond my wildest dreams because I thought we’d find things that would block oligodendrocyte development,” he says. “There are far more ways to block something than promote it.”

A chemical that promotes the development of myelin-forming oligodendrocytes may point the way toward therapies for remyelination—which could be beneficial for diseases like multiple sclerosis in which myelin abnormally degrades and results in nervous system dysfunction. Appel is hoping to pursue this lead with a biotech company to determine whether this compound or others like it might be feasible therapeutic targets.

“We need to determine whether this (compound) can direct differentiation of multipotent stem cells into the oligodendrocyte pathway,” he says. If so, Appel predicts this compound might become a “super-wonder-drug.”

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