Abstract
Although originally restricted to their structural role as major constituents of membranes, lipids are now well-defined actors to integrate intracellular or extracellular signals. Accordingly, it has been known for decades that lipids, especially those coming from diet, are important to maintain normal physiological functions and good health. This is especially the case to maintain proper cognitive functions and avoid neuronal degeneration. But besides this empiric knowledge, the exact molecular nature of lipids in cellular signaling, as well as their precise mode of action are only starting to emerge. The recent development of novel pharmacological, molecular, cellular and genetic tools to study lipids in vitro and in vivo has contributed to this improvement in our knowledge. Among these important lipids, phosphatidic acid (PA) plays a unique and central role in a great variety of cellular functions. This article will review the different findings illustrating the involvement of PA generated by phospholipase D (PLD) and diacylglycerol kinases (DGK) in the different steps of neuronal development and neurosecretion. We will also present lipidomic evidences indicating that different species of PA are synthesized during these two key neuronal phenomena.
Highlights
Normal brain function requires the establishment of specific neuronal networks mediated by synapses
Using the cell culture models of PC12 cells treated by neuronal growth factor (NGF), which have been widely used as a model to assess neurite outgrowth, we found that the phosphatidic acid (PA) sensor Spo20p-GFP accumulated at the plasma membrane following NGF stimulation as well as at the tips of growing neurites
Expression of phosphomimetic PLD1(T147D) or PLD1 (T147E) mutants rescued the inhibition of neurite outgrowth in PC12 cells silenced for RSK2, revealing that PLD1 is a major target for RSK2 in neurite formation and allowing us to propose that the loss of function mutations in RSK2 that leads to Coffin-Lowry syndrome (CLS) and neuronal deficits are related to defects in neuronal growth due to impaired RSK2-dependent PLD1 activity resulting in a reduced vesicle fusion rate and membrane supply
Summary
Normal brain function requires the establishment of specific neuronal networks mediated by synapses (i.e. structures allowing chemical or electrical communication between neurons). During their development, neurons exhibit various morphological and structural changes including axon and dendrite outgrowth, dendritic branching and ramification and spine development that allow synapse formation and maintenance, which are critical events in the establishment of neuronal networks (Dotti et al, 1988). Neuronal development and maturation require plasma membrane expansion and rearrangement provided essentially by two membrane trafficking mechanisms: exocytosis and endocytosis (Gasman and Vitale, 2017). It is tempting to speculate that specific lipids and their dynamics are critically important for membrane reorganization and neuronal development. We will present our recent findings suggesting that various PA species are differently synthetized during neurite outgrowth and neurosecretion
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