TY - JOUR
T1 - The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and Is Essential for Sensory Neuron Survival and Function
AU - Tanaka, Yosuke
AU - Niwa, Shinsuke
AU - Dong, Ming
AU - Farkhondeh, Atena
AU - Wang, Li
AU - Zhou, Ruyun
AU - Hirokawa, Nobutaka
N1 - Funding Information:
We thank Jun-ichi Miyazaki (Osaka University) for providing the CAG-Cre transgenic mice; Lou Reichardt (University of California, San Francisco) for the Trk antibodies; Toshiyuki Yoneda (Osaka University) and Masako Nakanishi (Wakayama Medical University) for the TRPV1-F11 cells; Akio Sekigawa and Masaki Takahashi (ZEISS) for SR-SIM and Airyscan microscopy; Yoshinobu Shimazawa (Nissan-Kagaku) for qRT-PCR; and Yosuke Takei, Noriko Homma, Tadayuki Ogawa, Fang Xu, Wenxing Yang, Momo Morikawa, Masaharu Yoshihara, Fumiyoshi Ishidate, Hiromi Sato, Nobuhisa Onouchi, Takeshi Akamatsu, Haruyo Fukuda, and all members of the N.H. lab for technical help and valuable discussions. This study was supported by a grant-in-aid for specially promoted research and a grant-in-aid for scientific research (S) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to N.H.).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6/15
Y1 - 2016/6/15
N2 - KIF1A is a major axonal transport motor protein, but its functional significance remains elusive. Here we show that KIF1A-haploinsufficient mice developed sensory neuropathy. We found progressive loss of TrkA(+) sensory neurons in Kif1a+/- dorsal root ganglia (DRGs). Moreover, axonal transport of TrkA was significantly disrupted in Kif1a+/- neurons. Live imaging and immunoprecipitation assays revealed that KIF1A bound to TrkA-containing vesicles through the adaptor GTP-Rab3, suggesting that TrkA is a cargo of the KIF1A motor. Physiological measurements revealed a weaker capsaicin response in Kif1a+/- DRG neurons. Moreover, these neurons were hyposensitive to nerve growth factor, which could explain the reduced neuronal survival and the functional deficiency of the pain receptor TRPV1. Because phosphatidylinositol 3-kinase (PI3K) signaling significantly rescued these phenotypes and also increased Kif1a mRNA, we propose that KIF1A is essential for the survival and function of sensory neurons because of the TrkA transport and its synergistic support of the NGF/TrkA/PI3K signaling pathway.
AB - KIF1A is a major axonal transport motor protein, but its functional significance remains elusive. Here we show that KIF1A-haploinsufficient mice developed sensory neuropathy. We found progressive loss of TrkA(+) sensory neurons in Kif1a+/- dorsal root ganglia (DRGs). Moreover, axonal transport of TrkA was significantly disrupted in Kif1a+/- neurons. Live imaging and immunoprecipitation assays revealed that KIF1A bound to TrkA-containing vesicles through the adaptor GTP-Rab3, suggesting that TrkA is a cargo of the KIF1A motor. Physiological measurements revealed a weaker capsaicin response in Kif1a+/- DRG neurons. Moreover, these neurons were hyposensitive to nerve growth factor, which could explain the reduced neuronal survival and the functional deficiency of the pain receptor TRPV1. Because phosphatidylinositol 3-kinase (PI3K) signaling significantly rescued these phenotypes and also increased Kif1a mRNA, we propose that KIF1A is essential for the survival and function of sensory neurons because of the TrkA transport and its synergistic support of the NGF/TrkA/PI3K signaling pathway.
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U2 - 10.1016/j.neuron.2016.05.002
DO - 10.1016/j.neuron.2016.05.002
M3 - Article
C2 - 27263974
AN - SCOPUS:84973911461
SN - 0896-6273
VL - 90
SP - 1215
EP - 1229
JO - Neuron
JF - Neuron
IS - 6
ER -