As axons grow past intermediate targets, they change their responsiveness to guidance cues. Local upregulation of receptor expression is involved, but the mechanisms for this are not clear. Here protein synthesis is traced within individual axons by introducing RNAs encoding visualizable reporters. Individual severed axons and growth cones can translate proteins and also export them to the cell surface. As axons reach the spinal cord midline, EphA2 is among the receptors upregulated on at least some distal axon segments. Midline reporter upregulation is recapitulated by part of the EphA2 mRNA 3' untranslated region, which is highly conserved and includes known translational control sequences. These results show axons contain all the machinery for protein translation and cell surface expression, and they reveal a potentially general and flexible RNA-based mechanism for regulation localized within a subregion of the axon.

Highly sulfated proteoglycans are correlated with axon boundaries in the developing central nervous system which suggests that these molecules affect neural pattern formation. In the developing mammalian retina, gradual regression of chondroitin sulfate may help control the onset of ganglion cell differentiation and initial direction of their axons. Changes induced by the removal of chondroitin sulfate from intact retinas in culture confirm the function of chondroitin sulfate in retinal histogenesis.

Summary Extracellular signals regulate protein translation in many cell functions. A key advantage of control at the translational level is the opportunity to regulate protein synthesis within specific cellular subregions. However, little is known about mechanisms that may link extracellular cues to translation with spatial precision. Here we show that a transmembrane receptor, DCC, forms a binding complex containing multiple translation components, including eukaryotic initiation factors, ribosomal large and small subunits, and monosomes. In neuronal axons and dendrites DCC colocalizes in particles with translation machinery, and newly synthesized protein. The extracellular ligand netrin promoted DCC-mediated translation and disassociation of translation components. The functional and physical association of a cell surface receptor with the translation machinery leads to a generalizable model for localization and extracellular regulation of protein synthesis, based on a transmembrane translation regulation complex.

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and Program in Neuroscience show that failure to regenerate is not purely an intrinsic Harvard Medical School deficit of CNS neurons, and is blocked by the CNS envi-Boston, Massachusetts 02115 ronment. Two main sites have been considered for the location Diagnosis: You should say of him: "One having a crushed of CNS factors that might inhibit axon regeneration (Figvertebra in his neck; he is unconscious of his two arms, ure 1). One site is the scar that forms at the region of his two legs, he is speechless. An ailment not to be injury. Following CNS injury the central area of necrosis treated." is infiltrated by glia and other nonneuronal cells, and a -Edwin Smith Surgical Papyrus, c. 2500-1600 B.C. fibrous scar forms. Axons do not extend through the scar and appear to be inhibited by it, with the axon tips forming club-like structures that can remain in place for Unfortunately, little has changed clinically in the several months or even years. Molecular components that may thousand years since this anonymous author gave us contribute to this inhibitory activity include chondroitin the first known descriptions of the tragic consequences sulfate proteoglycans (CSPG), tenascin, and semaphoof central nervous system (CNS) injury, and the limited rin-3A, which are upregulated in the region of scarring therapeutic options (Breasted, 1930). Today, it is estiand are inhibitory to axon growth in culture (Letourneau mated that more than 250,000 Americans have spinal et al., 1994; Davies et al., 1999; Pasterkamp et al., 1999, cord injuries, with 11,000 new cases every year (Berkoand references therein). Moreover, glial scar tissue witz et al., 1998). When axonal connections are damaged placed in culture can be converted to a permissive subin the adult brain or spinal cord, they show an extremely strate by enzymatic removal of glycosaminoglycans, limited ability to regenerate, even though axons can supporting the idea that CSPG is an important compogrow and regenerate efficiently in the embryonic CNS, nent. It is worth bearing in mind that proteoglycans bind and in the adult peripheral nervous system. What are many other molecules, and their role could be as a scafthe reasons for this selective shutdown of regeneration fold that presents molecular cues to the responding cell. in the adult CNS? Factors that may play a role can be The other main proposal is that inhibitors would be grouped in two categories: intrinsic properties of CNS broadly distributed in the myelin that ensheaths axons neurons that may make them incapable of regenerating, in white matter tracts of the adult CNS. Supporting this or extrinsic factors in the environment that may influence idea, the loss of regeneration potential during developaxon growth positively or negatively (reviewed by Horner ment correlates roughly with the onset of myelination. and Gage, 2000). Here, we focus on extrinsic negative Moreover, myelin carpets or oligodendrocytes, the cells factors, particularly recent studies of the inhibitory molethat produce CNS myelin, are poor substra...

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