Phosphatidylinositol-4-Phosphate 5-Kinases and Phosphatidylinositol 4,5-Bisphosphate Synthesis in the Brain

The predominant pathway for phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P-2) synthesis is thought to be phosphorylation of phosphatidylinositol 4-phosphate at the 5 position of the inositol ring by type I phosphatidylinositol phosphate kinases (PIPK): PIPKI alpha, PIPKI beta, and PIPKI gamma. PIPKI gamma has been shown to play a role in PI(4,5)P-2 synthesis in brain, and the absence of PIPKI gamma is incompatible with postnatal life. Conversely, mice lacking PIPKI alpha or PIPKI beta (isoforms are referred to according to the nomenclature of human PIPKIs) live to adulthood, although functional effects in specific cell types are observed. To determine the contribution of PIPKI alpha and PIPKI beta to PI(4,5)P-2 synthesis in brain, we investigated the impact of disrupting multiple PIPKI genes. Our results show that a single allele of PIPKI gamma, in the absence of both PIPKI alpha and PIPKI beta, can support life to adulthood. In addition, PIPKI alpha alone, but not PIPKI beta alone, can support prenatal development, indicating an essential and partially overlapping function of PIPKI alpha and PIPKI gamma during embryogenesis. This is consistent with early embryonic expression of PIPKI alpha and PIPKI gamma but not of PIPKI beta. PIPKI beta expression in brain correlates with neuronal differentiation. The absence of PIPKI beta does not impact embryonic development in the PIPKI gamma knock-out (KO) background but worsens the early postnatal phenotype of the PIPKI gamma KO (death occurs within minutes rather than hours). Analysis of PIP2 in brain reveals that only the absence of PIPKI gamma significantly impacts its levels. Collectively, our results provide new evidence for the dominant importance of PIPKI gamma in mammals and imply that PIPKI alpha and PIPKI beta function in the generation of specific PI(4,5)P-2 pools that, at least in brain, do not have a major impact on overall PI(4,5)P-2 levels.