Cytoplasmic p21 (green) promotes neurite outgrowth.

Newborns seem to do much better than adults in healing injuries to their central nervous systems. At the cellular level, this is because inhibitory molecules in the adult central nervous system prevent neurons from extending their axons and dendrites, but the neurons in embryos and newborns are apparently insensitive to these inhibitors. Now, Tanaka et al., reporting on page 321, have uncovered the molecular mechanism underlying this change in sensitivity. The findings suggest a new approach for developing therapies for brain and spinal cord injuries.

Analyzing chick retinal neurons, the authors found that the differentiation of newborn neurons is associated with cytoplasmic expression of p21Cip1/WAF1, a protein best known as a nuclear-localized cell cycle inhibitor. Ectopic expression of p21Cip1/WAF1 lacking its nuclear localization sequence promotes neurite outgrowth, and the protein strongly inhibits Rho kinase in a dose-dependent manner.

As neurite outgrowth inhibitors like myelin-associated glycoprotein and tumor necrosis factor were previously shown to signal through Rho and Rho kinase, cytoplasmic p21Cip1/WAF1 appears to target the common pathway of these inhibitory signals. Inducing cytoplasmic p21Cip1/WAF1 expression in adult neurons might therefore make the neurons “younger,” permitting them to extend neurites to repair an injury. ▪