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Developmental Decline in Neuronal Regeneration by the Progressive Change of Two Intrinsic Timers

Science  19 Apr 2013:
Vol. 340, Issue 6130, pp. 372-376
DOI: 10.1126/science.1231321

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Our neurons regenerate better when we are young than when we are more mature. Studying the mechanosensory anterior ventral microtubule (AVM) neuron of the nematode Caenorhabditis elegans, Zou et al. (p. 372; see the Perspective by Nix and Bastiani) found that worms lacking microRNA machinery had unusually robust axon regeneration and youthful-looking growth cones. Under- and overexpression of let-7 microRNA confirmed its involvement in depressing axon regeneration.

Abstract

Like mammalian neurons, Caenorhabditis elegans neurons lose axon regeneration ability as they age, but it is not known why. Here, we report that let-7 contributes to a developmental decline in anterior ventral microtubule (AVM) axon regeneration. In older AVM axons, let-7 inhibits regeneration by down-regulating LIN-41, an important AVM axon regeneration–promoting factor. Whereas let-7 inhibits lin-41 expression in older neurons through the lin-41 3′ untranslated region, lin-41 inhibits let-7 expression in younger neurons through Argonaute ALG-1. This reciprocal inhibition ensures that axon regeneration is inhibited only in older neurons. These findings show that a let-7–lin-41 regulatory circuit, which was previously shown to control timing of events in mitotic stem cell lineages, is reutilized in postmitotic neurons to control postdifferentiation events.

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