Abstract
Netrins, a family of secreted molecules, play important roles in axon pathfinding during nervous system development. Although phosphatidylinositol signaling has been implicated in this event, how netrin-1 regulates phosphatidylinositol signaling remains poorly understood. Here we provide evidence that netrin-1 stimulates phosphatidylinositol bisphosphate hydrolysis in cortical neurons. This event appears to be mediated by DCC (deleted in colorectal cancer), but not neogenin or Unc5h2. Netrin-1 induces phospholipase Cgamma (PLCgamma) tyrosine phosphorylation. Inhibition of PLC activity attenuates netrin-1-induced cortical neurite outgrowth. These results suggest that netrin-1 regulates phosphatidylinositol turnover and demonstrate a crucial role of PLC signaling in netrin-1-induced neurite elongation.
Highlights
DCC and Unc5 proteins are transmembrane proteins without any obvious catalytic activity, and it remains unknown exactly how they initiate downstream signaling to mediate or regulate axonal outgrowth and guidance
Netrin-1 Stimulation of PLC Signaling in a Time-dependent Manner— To address whether netrin-1 regulates PLC signaling, we measured PLCmediated PIP2 hydrolysis in cultured rat cortical neurons in response to netrin-1
Netrin-1-induced growth cone turning [27], with a different time course than that of netrin-1 induction of PLC␥ phosphorylation. These results suggest that tyrosine phosphorylation of PLC␥ by netrin-1 may not be focal adhesion kinase (FAK)-dependent, which is in line with the observation that FAK is not required for netrin-1-induced PIP2 hydrolysis
Summary
DCC and Unc proteins are transmembrane proteins without any obvious catalytic activity, and it remains unknown exactly how they initiate downstream signaling to mediate or regulate axonal outgrowth and guidance. Pharmacological inhibition of extracellular signal-regulated kinase (ERK) attenuates netrin-1-induced neurite outgrowth and growth cone turning [16, 17]. Phosphoinositides are quantitatively minor phospholipids of cell membranes, but their metabolism is highly active and tightly regulated. Using Xenopus growth cone-turning assays, Poo and colleagues [27] have demonstrated that perturbation of phospholipase C␥ (PLC␥) activity by pretreatment with brain-derived neurotrophic factor (BDNF) attenuates netrin-1-induced neurite outgrowth. PLC␥ is implicated in netrin-1-induced growth cone guidance, exactly how netrin-1 regulates this signaling event and its role in netrin-1-induced neurite outgrowth remain largely unknown. Inhibition of PLC activity by U73122 attenuated netrin1-induced neurite elongation These results demonstrate a crucial role of PLC signaling in netrin-1 induced neurite outgrowth
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