The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and Is Essential for Sensory Neuron Survival and Function.
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.
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Yosuke
Y
Tanaka
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Shinsuke
S
Niwa
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ming
M
Dong
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Atena
A
Farkhondeh
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Li
L
Wang
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ruyun
R
Zhou
Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Center of Excellence in Genome Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Electronic address: hirokawa@m.u-tokyo.ac.jp.
Nobutaka
N
Hirokawa
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D002211:Capsaicin / Q000494:pharmacology; D002470:Cell Survival; D005727:Ganglia, Spinal / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D016547:Kinesins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000502:physiology*
D002211:Capsaicin; D016547:Kinesins; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; C490576:Kif1a protein, mouse