Once our brain and spinal cord expand from a single band of cells into an incredibly intricate neural weave during embryonic development, we mammals are never again able to make new motor neurons -- the nerve cells that signal all muscles to move. That, however, is not the case with zebrafish. These little fresh water cyprinics, of which I have at least a dozen in my living room aquarium, are able to create new motor neurons their entire lives. In fact, a completely lesioned spinal cord or optic nerve of a zebra fish will, on its own, regain full function.
What that means is that the fish can somehow switch on a growth mechanism to create these new cells and guide them along to make the right connection. What if this mechanism could be found in humans and, once activated, promote nerve regeneration? That’s the focus of the work of Catherina Becker, Ph.D., and Thomas Becker, Ph.D., at the University of Edinburgh.
The Beckers have been working with these fish for a long time. In fact, they were funded by the Reeve Foundation ten years ago to look at axon regeneration in zebrafish related to a molecule called L1. They published a 2004 paper
on functional recovery in the fish with Melitta Schachner (they were all in Hamburg Germany at the time), who discovered L1 in 1987.
Slight digression: For a time, L1 had the buzz of possibility. It was licensed by Schachner to Acorda Therapeutics and was once listed in the company’s product pipeline; Schachner was until recently one of Acorda’s science advisors. Anyway, the idea was to take a soluble batch of L1 (which is now available commercially) and basically squirt it into spinal cord lesions. In experiments, that process neutralized inhibitors and thus promoted regeneration. While no human trials are on the horizon, Schachner is still working with zebrafish and molecular signaling in a system that self-repairs, now at Rutgers in New Jersey.
The latest Becker paper
we’re going to talk about features a signal protein called Notch 1 that repels regeneration in the fish. Their study, published last week in the Journal of Neuroscience, found that production of motor neurons could be increased in adult zebrafish using a drug that blocks the pathway for Notch.
The Becker team narrowed in on progenitor cells – cells that are have the genetic disposition to become motor neurons. They discovered that when Notch 1 was over-expressed, signals emerged that stopped the progenitor cells from becoming neurons. Logically, they turned to chemistry to prevent Notch 1 from sending the stop signals. And the fish could then make lots more new neurons; muting the Notch1 protein lead to an increase in production of progenitor cells and then motor neurons in the fish.
Humans have progenitor cells similar to those found in zebrafish, and Notch is preserved up the evolutionary tree; but our cells lose the ability to make the transition to full neurons. Catherina Becker muses this: "If we can find out more about the cell mechanisms involved in zebrafish to make motor neurons, we could potentially manipulate these pathways in humans with the hope of being able to generate new motor neurons."