The Phosphoinositide Kinase PIKfyve Is Vital in Early Embryonic Development PREIMPLANTATION LETHALITY OF PIKfyve−/− EMBRYOS BUT NORMALITY OF PIKfyve+/− MICE

摘要: Gene mutations in the phosphoinositide-metabolizing enzymes are linked to various human diseases. In mammals, PIKfyve synthesizes PtdIns(3,5)P2 and PtdIns5P lipids that regulate endosomal trafficking responses extracellular stimuli. The consequence of pikfyve gene ablation mammals is unknown. To clarify importance lipid products, this study, we have characterized first mouse model with global deletion using Cre-loxP approach. We report nearly all PIKfyveKO/KO mutant embryos died before 32–64-cell stage. Cultured fibroblasts derived from PIKfyveflox/flox rendered pikfyve-null by Cre recombinase expression displayed severely reduced DNA synthesis, consistent impaired cell division causing early embryo lethality. heterozygous PIKfyveWT/KO mice were born at expected Mendelian ratio developed into adulthood. ostensibly normal several other vivo, ex vitro criteria despite fact their levels protein enzymatic activity cells tissues 50–55% lower than those wild-type mice. Consistently, steady-state products selectively decreased, but reduction (35–40%) was 10–15% less based on reduction. nonlinear decrease versus potential mechanism(s) discussed herein, may explain how one functional allele able support demands for PtdIns(3,5)P2/PtdIns5P synthesis during life. Our data also shed light known disorder PIKFYVE mutations.