TY - JOUR
T1 - Axon Regeneration Pathways Identified by Systematic Genetic Screening in C. elegans
AU - Chen, Lizhen
AU - Wang, Zhiping
AU - Ghosh-Roy, Anindya
AU - Hubert, Thomas
AU - Yan, Dong
AU - O'Rourke, Sean
AU - Bowerman, Bruce
AU - Wu, Zilu
AU - Jin, Yishi
AU - Chisholm, Andrew D.
N1 - Funding Information:
We thank Alison Hughes, Niousha Saghafi, Amanda Rajapaksa, Sunny Sun, Peg Scott, Caroline Yu, Laura Toy, and other members of our labs for strain construction. We thank Johann Gagnon-Bartsch and Terry Speed for advice on statistical analysis; Cori Bargmann, Gian Garriga, and Erik Jorgensen for reagents; Chris Fang-Yen for the bead immobilization protocol; and Emily Troemel for comments on the manuscript. We thank the C. elegans Gene Knockout Consortium and the Japanese National Bioresource Project for deletion mutations, and the Caenorhabditis Genetics Center for strains. L.C., A.D.C., and Y.J. designed the screen. Z. Wu performed axotomy, imaging, and technical development. L.C. constructed strains and analyzed efa-6 ; Z. Wang analyzed slt-1/sax-3 signaling. A.G.-R. designed and performed MT imaging and analysis. L.C., Z. Wang, T.H., A.G.-R. and D.Y. contributed to the screen and analyzed the results. S.O'R. and B.B. provided reagents and unpublished data for efa-6 . L.C., Z. Wang, Y.J., and A.D.C. wrote the manuscript. Z. Wang is a Fellow of the Jane Coffin Childs Memorial Fund. Z. Wu is an Associate and Y.J. is an Investigator of the Howard Hughes Medical Institute. Supported by grants from the NIH to B.B. (R01 GM049859 and GM058017), Y.J. (R01 NS035546), and A.D.C. (R01 NS057317).
PY - 2011/9/22
Y1 - 2011/9/22
N2 - The mechanisms underlying the ability of axons to regrow after injury remain poorly explored at the molecular genetic level. We used a laser injury model in Caenorhabditis elegans mechanosensory neurons to screen 654 conserved genes for regulators of axonal regrowth. We uncover several functional clusters of genes that promote or repress regrowth, including genes classically known to affect axon guidance, membrane excitability, neurotransmission, and synaptic vesicle endocytosis. The conserved Arf Guanine nucleotide Exchange Factor (GEF), EFA-6, acts as an intrinsic inhibitor of regrowth. By combining genetics and in vivo imaging, we show that EFA-6 inhibits regrowth via microtubule dynamics, independent of its Arf GEF activity. Among newly identified regrowth inhibitors, only loss of function in EFA-6 partially bypasses the requirement for DLK-1 kinase. Identification of these pathways significantly expands our understanding of the genetic basis of axonal injury responses and repair.
AB - The mechanisms underlying the ability of axons to regrow after injury remain poorly explored at the molecular genetic level. We used a laser injury model in Caenorhabditis elegans mechanosensory neurons to screen 654 conserved genes for regulators of axonal regrowth. We uncover several functional clusters of genes that promote or repress regrowth, including genes classically known to affect axon guidance, membrane excitability, neurotransmission, and synaptic vesicle endocytosis. The conserved Arf Guanine nucleotide Exchange Factor (GEF), EFA-6, acts as an intrinsic inhibitor of regrowth. By combining genetics and in vivo imaging, we show that EFA-6 inhibits regrowth via microtubule dynamics, independent of its Arf GEF activity. Among newly identified regrowth inhibitors, only loss of function in EFA-6 partially bypasses the requirement for DLK-1 kinase. Identification of these pathways significantly expands our understanding of the genetic basis of axonal injury responses and repair.
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U2 - 10.1016/j.neuron.2011.07.009
DO - 10.1016/j.neuron.2011.07.009
M3 - Article
C2 - 21943602
AN - SCOPUS:80053104351
SN - 0896-6273
VL - 71
SP - 1043
EP - 1057
JO - Neuron
JF - Neuron
IS - 6
ER -