Elevating Growth Factor Responsiveness and Axon Regeneration by Modulating Presynaptic Inputs

Yiling Zhang, Philip R. Williams, Anne Jacobi, Chen Wang, Anurag Goel, Arlene A. Hirano, Nicholas C. Brecha, Daniel Kerschensteiner, Zhigang He

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Despite robust effects on immature neurons, growth factors minimally promote axon regeneration in the adult central nervous system (CNS). Attempting to improve growth-factor responsiveness in mature neurons by dedifferentiation, we overexpressed Lin28 in the retina. Lin28-treated retinas responded to insulin-like growth factor-1 (IGF1) by initiating retinal ganglion cell (RGC) axon regeneration after axotomy. Surprisingly, this effect was cell non-autonomous. Lin28 expression was required only in amacrine cells, inhibitory neurons that innervate RGCs. Ultimately, we found that optic-nerve crush pathologically upregulated activity in amacrine cells, which reduced RGC electrical activity and suppressed growth-factor signaling. Silencing amacrine cells or pharmacologically blocking inhibitory neurotransmission also induced IGF1 competence. Remarkably, RGCs regenerating across these manipulations localized IGF1 receptor to their primary cilia, which maintained their signaling competence and regenerative ability. Thus, our results reveal a circuit-based mechanism that regulates CNS axon regeneration and implicate primary cilia as a regenerative signaling hub.

Original languageEnglish
Pages (from-to)39-51.e5
JournalNeuron
Volume103
Issue number1
DOIs
StatePublished - Jul 3 2019

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