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Sci. Signal., 2 February 2010
Vol. 3, Issue 107, p. ec36
[DOI: 10.1126/scisignal.3107ec36]

EDITORS' CHOICE

Neuroscience Signaling Stop from the Inside

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Nogo-A is a member of a family of potent neurite growth inhibitors. One of the active regions is the C-terminal Nogo-66 domain, which is shared by two other family members and which binds the cell surface receptor NgR. A central region called Nogo{Delta}20 is specific to Nogo-A and exhibits inhibitor activity that is independent of NgR. Joset et al. found that when applied to a neuronal cell line (PC12 cells), cultured hippocampal cells, or cultured dorsal root ganglion (DRG) neurons, Nogo{Delta}20 was internalized through a macropinocytotic mechanism that required the activity of Pincher, a member of the Eps15 homology domain–containing proteins (EHDs). Inhibition of clathrin-mediated endocytosis or caveolin-mediated endocytosis did not block Nogo{Delta}20 internalization in PC12 cells. Overexpression of dominant-negative Pincher reduced growth cone collapse in hippocampal neurons treated with Nogo{Delta}20, and cerebellar granule neurons overexpressing the dominant-negative Pincher exhibited longer neurites in the presence of Nogo{Delta}20 than did untransfected cells exposed to Nogo{Delta}20. Nogo{Delta}20 is known to stimulate RhoA activity, and overexpression of dominant-negative Pincher reduced the Nogo{Delta}20-stimulated activation of Rho family members in PC12 cells. Nogo{Delta}20 was delivered to cell bodies of cultured DRG neurons through a process requiring microtubule-mediated retrograde transport, and this retrograde transport was blocked by overexpression of dominant-negative Pincher. Rho activity was increased in the DRG neurites shortly after Nogo{Delta}20 application (30 minutes), and at later times (6 hours) increased Rho activity was evident in the cell bodies. In the neurites, active Rho colocalized with Nogo{Delta}20-positive vesicles, leading the authors to propose that active Rho was delivered to cell bodies as part of Nogo{Delta}20 signaling endosomes or Nogo{Delta}20 signalosomes. In support of this hypothesis, endosomal fractions from PC12 cells exposed to Nogo{Delta}20 exhibited higher amounts of active Rho than did fractions from untreated cells.

A. Joset, D. A. Dodd, S. Halegoua, M. E. Schwab, Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling. J. Cell Biol. 188, 271–285 (2010). [Abstract] [Full Text]

Citation: N. R. Gough, Signaling Stop from the Inside. Sci. Signal. 3, ec36 (2010).



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