TY - JOUR
T1 - Elevating Growth Factor Responsiveness and Axon Regeneration by Modulating Presynaptic Inputs
AU - Zhang, Yiling
AU - Williams, Philip R.
AU - Jacobi, Anne
AU - Wang, Chen
AU - Goel, Anurag
AU - Hirano, Arlene A.
AU - Brecha, Nicholas C.
AU - Kerschensteiner, Daniel
AU - He, Zhigang
N1 - Funding Information:
We thank Drs. J. Sanes and S. Hegarty for critical reading of the manuscript. This study was supported by grants from the William Randolph Hearst Foundation (P.R.W.), NEI (to N.C.B.), and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to Z.H.). This work was supported in part by Career Scientist Award ( 14F-RCS-004 ) from the United States Department of Veterans Affairs . IDDRC and viral cores supported by the NIH ( P30 HD018655 and P30 EY012196 ) were used for this study. D.K. was supported by a grant from the NEI ( R01EY027411 ).
Funding Information:
We thank Drs. J. Sanes and S. Hegarty for critical reading of the manuscript. This study was supported by grants from the William Randolph Hearst Foundation (P.R.W.), NEI (to N.C.B.), and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to Z.H.). This work was supported in part by Career Scientist Award (14F-RCS-004) from the United States Department of Veterans Affairs. IDDRC and viral cores supported by the NIH (P30 HD018655 and P30 EY012196) were used for this study. D.K. was supported by a grant from the NEI (R01EY027411). Y.Z. P.R.W. and C.W. performed regeneration, survival, and all other histological procedures. Y.Z. and P.R.W. performed microscopy and image analysis. A.J. performed backtracing surgeries. P.R.W. A.G. and D.K. performed and analyzed multielectrode array experiments. A.A.H. and N.C.B. provided Cx57-Cre transgenic mice. P.R.W. prepared figures. P.R.W. and Z.H. wrote the manuscript and designed experiments. The authors have no competing interests to declare.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/7/3
Y1 - 2019/7/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85068195865&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2019.04.033
DO - 10.1016/j.neuron.2019.04.033
M3 - Article
C2 - 31122676
AN - SCOPUS:85068195865
SN - 0896-6273
VL - 103
SP - 39-51.e5
JO - Neuron
JF - Neuron
IS - 1
ER -