Sci. Signal., 18 May 2010
Neuroscience Found in Translation?
Elizabeth M. Adler
Science Signaling, AAAS, Washington, DC 20005, USA
Localized translation enables the regulation of gene expression in specific subcellular compartments (see Martin). In neurons, for example, localized translation in dendrites had been implicated in processes that may contribute to learning and memory, and localized translation in growth cones has been implicated in axon guidance. Tcherkezian et al. explored the mechanisms whereby extracellular signals regulate local protein translation in neurons, focusing on DCC (deleted in colorectal cancer), a receptor for netrin (a secreted axon growth and guidance factor). DCC colocalized with ribosomal markers and newly synthesized protein in filopodial tips of cultured commissural neurons and with the postsynaptic marker PSD-95, eIF4E (eukaryotic translation initiation factor 4E), and newly synthesized protein in dendrites of cultured hippocampal neurons. Translation initiation factors and proteins of the ribosomal small and large subunits coprecipitated with DCC transfected into 293 cells, which lack endogenous netrin receptors, and with endogenous DCC from embryonic spinal cord, but not with a DCC mutant lacking the cytoplasmic domain (DCC-cyto). Sucrose gradient velocity sedimentation revealed cosedimentation of DCC with the large and small ribosomal subunits and with monosomes rather than polysomes. DCC transfection led to increased translation and protein synthesis in netrin-secreting 293 cells, and netrin reduced the association of DCC with the translational machinery. Moreover, netrin increased the accumulation of newly synthesized protein associated with DCC in filopodia of cultured commissural neurons. DCC-cyto did not promote translation, and further analysis implicated a conserved motif, P1, in mediating the association of DCC with the translational machinery and with netrin-mediated translation. Recombinant ribosomal protein L5 bound to recombinant DCC cytoplasmic domain; deletion analysis implicated P1 in L5 binding, and, in chick spinal cord explants, a form of DCC lacking P1 that interfered with translation decreased growth of commissural axons toward a netrin source. The authors propose that DCC associates with the translation initiation machinery and that netrin stimulates DCC signaling to promote the release of ribosomes and translation initiation factors from DCC and thereby the formation of actively elongating polysomes.
J. Tcherkezian, P. A. Brittis, F. Thomas, P. P. Roux, J. G. Flanagan, Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 141, 632–644 (2010). [PubMed]
K. C. Martin, Anchoring local translation in neurons. Cell 141, 566–568 (2010). [Online Journal]
Citation: E. M. Adler, Found in Translation? Sci. Signal. 3, ec147 (2010).
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