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Mutations that cause defects in levels of the signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2 ] lead to profound neurodegeneration in mice. Moreover, mutations in human FIG4 predicted to lower PI(3,5)P2 levels underlie Charcot–Marie–Tooth type 4J neuropathy and are present in selected cases of amyotrophic lateral sclerosis. In yeast and mammals, PI(3,5)P2 is generated by a protein complex that includes the lipid kinase Fab1/Pikfyve, the scaffolding protein Vac14, and the lipid phosphatase Fig4. Fibroblasts cultured fromVac14 −/− and Fig4−/− mouse mutants have a 50% reduction in the levels of PI(3,5)P2 , suggesting that there may be PIKfyve-independent pathways that generate this lipid. Here, we characterize aPikfyve gene-trap mouse (Pikfyve β -geo/β -geo), a hypomorph with ∼10% of the normal level of Pikfyve protein. shRNA silencing of the residualPikfyve transcript in fibroblasts demonstrated that Pikfyve is required to generate all of the PI(3,5)P2 pool. Surprisingly, Pikfyve also is responsible for nearly all of the phosphatidylinositol-5-phosphate (PI5P) pool. We show that PI5P is generated directly from PI(3,5)P2 , likely via 3′-phosphatase activity. Analysis of tissues from thePikfyve β -geo/β -geomouse mutants reveals that Pikfyve is critical in neural tissues, heart, lung, kidney, thymus, and spleen. Thus, PI(3,5)P2 and PI5P have major roles in multiple organs. Understanding the regulation of these lipids may provide insights into therapies for multiple diseases.

In vivo, Pikfyve generates PI(3,5)P 2 , which serves as both a signaling lipid and the major precursor for PI5P

In vivo, Pikfyve generates PI(3,5)P ₂ , which serves as both a signaling lipid and the major precursor for PI5P