The Nerve of Youth
Authors: Davenport R. John 
Published: August 2003

Nobody wants to have the brains of a baby, but having a newborn's nerves could be a boon in old age. Young neurons grow more readily than older ones, and a new study uncovers a mechanism. The findings reveal a control point for turning on and off nerve growth and a potential target for repairing damaged brain cells.
If neurons in adult brains didn't contain inhibitory molecules, they would sprout like weeds, disrupting connections and choking off normal brain function. Newborn nerve cells somehow override this arrest so that they can hook up with each other. Understanding what allows green neurons to spread could steer researchers toward ways to repair brain damage from injury or degenerative diseases. Previous studies showed that developing nerve cells crank up quantities of a protein called p21 when they dispatch feelers to find and connect with other nerves. Tanaka and colleagues wondered whether p21 underlies this activity.
The researchers first examined eye nerve cells from newly hatched chicks and looked for p21. Using fluorescent antibodies to label the protein, they found that the cytoplasm lights up at the same time that cells send out extensions called neurites. p21 is most famous for appearing in the nucleus, where it shuts down cell division, but scientists have recently discovered that it performs jobs in the cytoplasm as well. To probe deeper, Tanaka and colleagues engineered cultured nerve cells to produce a short version of p21--called ΔNLS-p21--that lacks its ticket to the nucleus. Almost half of the cells making ΔNLS-p21 developed long neurites, compared with only 15% of cells making complete p21. The results suggest that cytoplasmic p21 encourages nerve extension.
Previous studies revealed that blocking a protein called Rho kinase also increases neurite growth, so the researchers investigated whether ΔNLS-p21 quells Rho kinase. When they used antibodies to pull ΔNLS-p21 from the cells' innards, Rho kinase came along, suggesting that the two proteins bind in the cell. Rho kinase spurs other proteins to shut down nerve growth by decorating them with phosphate groups; further experiments showed that p21 impairs this activity in a test tube. The team also demonstrated that the complete p21 protein--which resides predominantly in the nucleus--carries with it fewer molecules of Rho kinase than the cytoplasmic form does. These and other findings support the idea that p21's ability to promote neuron growth by inhibiting Rho kinase depends on its location in the cell. Manipulating injured cells to produce p21 in the cytoplasm could help them recover, says study author and neuroscientist Toshihide Yamashita of Osaka University in Japan, although proof of that concept awaits further study.
The work is the first to reveal a natural protein inhibitor of Rho kinase, says molecular geneticist Liqun Luo of Stanford University in Palo Alto, California. Because p21 serves multiple functions in the cell, Rho kinase itself might be the better target for drug therapy, he adds. But understanding the signals that determine whether p21 goes to the nucleus or stays in the cytoplasm could reveal how graying nerves lose the resilience of youth.
--R. John Davenport

H. Tanaka, T. Yamashita, M. Asada, S. Mizutani, H. Yoshikawa, M. Tohyama, Cytoplasmic p21
Cip1/WAF1
regulates neurite remodeling by inhibiting Rho-kinase activity.
J. Cell Biol.
158
, 321-329 (2002).
[Abstract]
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