Brain-derived neurotrophic factor (BDNF) is known to promote neuronal survival and differentiation1 and to guide axon extension both in vitro2,3 and in vivo4. The BDNF-induced chemo-attraction of axonal growth cones requires Ca2+ signalling3, but how Ca2+ is regulated by BDNF at the growth cone remains largely unclear. Extracellular application of BDNF triggers membrane currents resembling those through TRPC (transient receptor potential canonical) channels in rat pontine neurons5 and in Xenopus spinal neurons6. Here, we report that in cultured cerebellar granule cells, TRPC channels contribute to the BDNF-induced elevation of Ca2+ at the growth cone and are required for BDNF-induced chemo-attractive turning. Several members of the TRPC family are highly expressed in these neurons, and both Ca2+ elevation and growth-cone turning induced by BDNF are abolished by pharmacological inhibition of TRPC channels, overexpression of a dominant-negative form of TRPC3 or TRPC6, or downregulation of TRPC3 expression via short interfering RNA. Thus, TRPC channel activity is essential for nerve-growth-cone guidance by BDNF.
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We thank T. Gudermann for providing the cDNA of DN-TRPC6; J. W. Putney for full-length hTRPC3; K. Groschner for DN-TRPC3; Q. Hu for technical support with confocal microscopy; J.-Y. Yu for cell culture; and Y.-J. Zhang for some biochemical assays. This work was supported by grants from Major State Basic Research Program and National Natural Science Foundation of China. X.-b.Y. was also supported by the Shanghai city government.
The authors declare that they have no competing financial interests.
Glutamate-induced attraction requires ionotropic glutamate receptors and L-type Ca2+ channel. (PDF 44 kb)
TRPC channels are not required for glutamate-induced growth cone attraction and Ca2+ elevation. (PDF 39 kb)
Specificity of TRPC antibodies. (PDF 341 kb)
Sequences for siRNA and primers. (DOC 38 kb)
Legends to accompany the above Supplementary Figures. (DOC 20 kb)
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Li, Y., Jia, Y., Cui, K. et al. Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature 434, 894–898 (2005). https://doi.org/10.1038/nature03477
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