摘要：SummaryDuring neurodevelopment, the growth cone deciphers directional information from extracellular guidance cues presented as shallow concentration gradients via signal amplification. However, it remains unclear how the growth cone controls this amplification process during its navigation through an environment in which basal cue concentrations vary widely. Here, we identified inositol 1,4,5-trisphosphate (IP3) receptor type 3 as a regulator of axonal sensitivity to guidance cuesin vitroandin vivo. Growth cones lacking the type 3 subunit are hypersensitive to nerve growth factor (NGF), an IP3-dependent attractive cue, and incapable of turning toward normal concentration ranges of NGF to which wild-type growth cones respond. This is due to globally, but not asymmetrically, activated Ca2+signaling in the hypersensitive growth cones. Remarkably, lower NGF concentrations can polarize growth cones for turning if IP3receptor type 3 is deficient. These data suggest a subtype-specific IP3receptor function in sensitivity adjustment during axon navigation.Graphical AbstractDisplay OmittedHighlights•IP3receptor type 3 (IP3R3) controls axonal sensitivity to IP3-based guidance cues•IP3R3−/−growth cones are not attracted to NGF due to global Ca2+responses•Lower NGF concentrations can polarize IP3R3−/−growth cones for attractive turning•NGF knockdownin vivocan revert abnormal trajectory of IP3R3−/−axonsBiological Sciences; Neuroscience; Molecular Neuroscience; Cellular Neuroscience
