The Coffin‐Lowry syndrome‐associated protein RSK2 regulates neurite outgrowth through phosphorylation of PLD1 and synthesis of phosphatidic acid, a membrane curving fusogenic lipid.

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Most of the mutations associated with mental retardation (MR) induce limited visible morphological alterations in brain organization and the molecular bases underlying the neuronal clinical features remain elusive. We show here that neurons cultured from mice deficient for ribosomal S6 kinase 2 (Rsk2), a model for the Coffin‐Lowry syndrome (CLS), exhibit a significant delay in development in a pattern very similar to that shown by neurons cultured from phospholipase D1 (Pld1) knockout mice. We found that gene silencing of Pld1 or Rsk2 as well as acute pharmacological inhibition of PLD1 or RSK2 strongly impaired neuronal growth factor (NGF)‐induced neurite outgrowth from PC12 cells. NGF triggered RSK2‐dependent phosphorylation of PLD1 leading to the synthesis of phosphatidic acid at the site of neurite growth. NGF‐induced neurite outgrowth and VAMP‐7 vesicle exocytosis was severely inhibited in PC12 cells silenced for RSK2 expression. However, expression of a phosphomimetic PLD1 mutant or provision of lysophosphatidic acid, an inverted cone‐shaped lipid that favors membrane curvature were able to rescue the growth defect in RSK2 silenced cells, revealing that PLD1 is the major target of RSK2 in neurite formation. We propose that the loss of function mutations in RSK2 that lead to CLS and neuronal deficits are related to defects in neuronal growth due to impaired RSK2‐dependent PLD1 activity.