When the longest cells in the body are injured at their farthest reaches, coordinating the cells' repair is no easy task. This is in part because these peripheral nerve cells can be extremely long -- up to one meter in adult humans -- which is a lot of distance for a molecular distress signal to cover in order to reach the "command center" of the cell's nucleus.
Scientists have believed this process to be even more challenging because their textbook understanding for many years has been that the axons -- the long extensions of nerve cells away from the main cell body containing the nucleus -- do not manufacture the proteins involved in the molecular signal themselves. Yet, in recent years, some scientists have begun to challenge that textbook understanding, with preliminary evidence that one key protein involved in setting off a distress signal for cellular repair, known as importin beta1, was locally produced in the axons. They just weren't sure how.
"Now these textbooks need to be rewritten," said Dr. Jeffery Twiss, a professor and head of the department of biology in Drexel University's College of Arts and Sciences. Twiss co-authored new research recently published in Neuron, led by collaborators from the Weizmann Institute of Science. "Our new research is one of the strongest indicators yet of molecular signaling from end to end in peripheral nerve cells."
These researchers have provided strong new evidence that the protein importin beta1 is indeed produced locally in the axons of peripheral nerve cells. They also found that the version of the protein, when found in the axon, is made using a different molecular recipe than the version found in the nucleus, where it performs different essential cell functions. These discoveries may help scientists better understand how subsequent steps operate in the distress signal and in nerve cell repair, so they can eventually control and enhance the process to speed up recovery from nerve injuries.
Finding this evidence was far from simple: Importins are so crucial in the cell's nucleus that even the smallest embryo could not survive without them. But Rotem Ben-Tov Perry, a research student at the Weizmann Institute who was lead author of the new study, found a way to distinguish the importin beta1 in the cell body from that in the axon: The axonal protein was apparently made from a longer version of messenger RNA, the cell's working recipe for building a protein. To see if they could selectively affect just the axonal version of the protein, the Weizmann researchers worked with Drexel's Twiss to take advantage of high precision knock-out technology. Rather than knocking a whole gene out of the system, they managed to remove one little piece of the messenger RNA's recipe for manufacturing importins- just the longer bit that sends the RNA to the axon.
Now they observed plenty of importin beta1 in the cell body, but none in the axons. With the axonal segment of RNA knocked out of the recipe for importin beta1, a mouse embryo still had the importin it needed near the nucleus of its cells to grow and develop into a living animal -- but it took much longer to recover from peripheral nerve injury. Genes that are normally active in response to nerve damage were activated to a lesser degree. All of this suggests that the importin beta1 that normally helps inform the extended nerve cell about injury is, indeed, produced locally in the axon -- and that this protein found in the axon is a key part of the nerve repair signaling process.
"The data shows conclusively that importin beta1 protein is produced in axons, Rotem's work has validated the importins' crucial role in nerve repair," said Dr. Michael Fainzilber, senior author and professor at the Weizmann Institute.
Twiss said that next steps will be to better describe how the signaling process involving importin beta1 delivers a signal to begin nerve cell repair and, ultimately, develop strategies to better control these molecular steps of the repair mechanisms to improve nerve cell regeneration after injury.
- Rotem Ben-Tov Perry, Ella Doron-Mandel, Elena Iavnilovitch, Ida Rishal, Shachar Y. Dagan, Michael Tsoory, Giovanni Coppola, Marguerite K. McDonald, Cynthia Gomes, Daniel H. Geschwind, Jeffery L. Twiss, Avraham Yaron, Mike Fainzilber. Subcellular Knockout of Importin β1 Perturbs Axonal Retrograde Signaling. Neuron, 2012; 75 (2): 294 DOI: 10.1016/j.neuron.2012.05.033
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