Growth cones make proteins, too

Abstract

Axons branch out from neurons as they respond to chemical cues in their extracellular environment. Until recently, many scientists did not believe that elongating axons could synthesize proteins locally. But in the past three years, this view has been largely overturned. One of the first clues that protein synthesis might occur in the growing tips of axons—the growth cones—came from morphological studies conducted over 30 years ago by Virginia Tennyson. In the mid-1960s, several electron microscopy studies of neurons had been published, but few of them focused on the growth cone. Tennyson, then a researcher at Columbia University, decided to examine the axons of fetal rabbit dorsal root neuroblasts at 11–12 days, a time in development when many growth cones are present. “I remember, I wanted to study growth cones,” recalls Tennyson. “I certainly was not expecting to see any ribosomes.” Tennyson observed clusters of particles along the length of an entire axon and in several growth cones. The particles were 150–250 A in diameter and morphologically identical to ribosomes (Tennyson, 1970). “The presence of ribosomes in the early embryonic axons suggests that protein synthesis may continue in these segments at a considerable distance from the perikaryon [neuron cell body],” Tennyson wrote in her 1970 paper. “Of course I had no evidence of protein synthesis at that time, so I did not want to make too much of that observation,” she says. Shortly after Tennyson's study, further ultrastructural analyses confirmed the presence of polyribosomes in growth cones of cultured neurons (Yamada et al., 1971; Bunge, 1973). Figure Ribosomes (arrows) turned up in axons. Since then, several studies have documented ribosomes, mRNA, translational initiation proteins, and protein synthesis in axons and growth cones. Douglas Campbell and Christine Holt (University of Cambridge) demonstrated that molecules that guide the growth of axons rapidly trigger protein synthesis in isolated retinal growth cones (Campbell and Holt, 2001). Inhibition of protein synthesis by translation blockers abolishes the response of these growth cones to guidance molecules. This and other studies (Brittis et al., 2002; Zheng et al., 2001) showed that, at least in vitro, fast, local synthesis of proteins not only occurs but is necessary for guiding axon growth in response to external cues. “In retrospect,” muses Holt, “it is surprising how remarkable everyone thought this was.” Brittis, P.A., et al. 2002. Cell. 110:223–235. [PubMed] Bunge, M.B. 1973. J. Cell Biol. 56:713–735. [PubMed] Campbell, D.S., and C.E. Holt. 2001. Neuron. 32:1013–1026. [PubMed] Tennyson, V.M. 1970. J. Cell Biol. 44:62–79. [PubMed] Yamada, K.M., et al. 1971. J. Cell Biol. 49:614–635. [PubMed] Zheng, J.Q., et al. 2001. J. Neurosci. 21:9291–9303. [PubMed]