Control of Neuronal Growth Cone Navigation by Asymmetric Inositol 1,4,5-Trisphosphate Signals

Measurements of its spatial profile reveal the crucial role of asymmetric IP3 signals in growth cone navigation. IP3 Points the Way During nervous system development, neurites navigate to their targets by responding to cues in the environment. Attractive or repulsive turning depends on the generation of asymmetric changes in Ca2+ within the growth cone of the developing neurite. The source of these intracellular Ca2+ signals is critical to determining whether the response is attractive (with the growth cone turning toward the side with increased Ca2+ concentration) or repulsive (with the growth cone turning away from the side with increased Ca2+ concentration). Here, Akiyama et al. show that attractive turning to nerve growth factor (NGF) depends on phospholipase C (PLC)–dependent generation of asymmetric changes in inositol 1,4,5-trisphosphate (IP3) and the ensuing IP3-induced Ca2+ release from the endoplasmic reticulum. Dissection of the pathway showed that the turning response required basal cAMP signaling upstream of asymmetric IP3-induced Ca2+ release and required basal phosphatidylinositol 3-kinase (PI3K)–dependent signaling downstream. Inositol 1,4,5-trisphosphate (IP3) is generally viewed as a global messenger that increases cytosolic calcium ion (Ca2+) concentration. However, the spatiotemporal dynamics of IP3 and the functional significance of localized IP3 production in cell polarity remain largely unknown. Here, we demonstrate the critical role of spatially restricted IP3 signals in axon guidance. We found that IP3 and ensuing Ca2+ signals were produced asymmetrically across growth cones exposed to an extracellular gradient of nerve growth factor (NGF) and mediated growth cone turning responses to NGF. Moreover, photolysis-induced production of IP3 on one side of a growth cone was sufficient to initiate growth cone turning toward the side with the higher concentration of IP3. Thus, locally produced IP3 encodes spatial information that polarizes the growth cone for guided migration.

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