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Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain

View ORCID ProfileEvan K. Noch, Isaiah Yim, View ORCID ProfileTeresa A. Milner, View ORCID ProfileLewis C. Cantley
doi: https://doi.org/10.1101/2020.01.29.925685
Evan K. Noch
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 413 69th St, New York, NY 10021 U.S.ADepartment of Neurology, Weill Cornell Medicine 1300 York Ave, New York, NY 10021 U.S.A.
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  • For correspondence: ekn9001@med.cornell.edu
Isaiah Yim
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 413 69th St, New York, NY 10021 U.S.A
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Teresa A. Milner
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065 U.S.A.Harold and Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Ave, New York, NY 10065 U.S.A.
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Lewis C. Cantley
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 413 69th St, New York, NY 10021 U.S.A
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Abstract

Phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) is critical for synaptic vesicle docking and fusion and generation of the second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. PI-4,5-P2 can be generated by two families of kinases: type 1 phosphatidylinositol-4-phosphate 5-kinases, encoded by PIP5K1A, PIP5K1B and PIP5K1C, and type 2 phosphatidylinositol-5-phosphate 4-kinases, encoded by PIP4K2A, PIP4K2B, and PIP4K2C. While the roles of the type 1 enzymes in brain function have been extensively studied, the roles of the type 2 enzymes are poorly understood. Using selective antibodies validated by genetic deletion of pip4k2a or pip4k2b in mouse brain, we characterized the location of the enzymes, PI5P4Kα and PI5P4Kß, encoded by these genes. In mice, we demonstrate that PI5P4Kα is expressed in adulthood, whereas PI5P4Kß is expressed early in development. PI5P4Kα localizes to white matter tracts, especially the corpus callosum, and at a low level in neurons, while PI5P4Kß is expressed in neuronal populations, especially hippocampus and cortex. Dual labeling studies demonstrate that PI5P4Kα co-localizes with the oligodendrocyte marker, Olig2, whereas PI5P4Kß co-localizes with the neuronal marker, NeuN. Immunohistochemical subcellular distribution studies demonstrate that PI5P4Kα and PI5P4Kß are expressed in the early endosome system. Ultrastructural analysis demonstrates that both kinases are contained in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission. Immunohistochemical analysis of macaque and human brain tissue demonstrate a conserved pattern for PI5P4Kα and PI5P4Kß. These results highlight the diverse cell-autonomous expression of PI5P4Kα and PI5P4Kß and support further exploration into their role in synaptic function in the brain.

Footnotes

  • Support: NIH grants DA08259, HL136520 (T.A.M). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R35CA197588. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 30, 2020.
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Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain
Evan K. Noch, Isaiah Yim, Teresa A. Milner, Lewis C. Cantley
bioRxiv 2020.01.29.925685; doi: https://doi.org/10.1101/2020.01.29.925685
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Distribution and localization of phosphatidylinositol 5-phosphate, 4-kinase alpha and beta in the brain
Evan K. Noch, Isaiah Yim, Teresa A. Milner, Lewis C. Cantley
bioRxiv 2020.01.29.925685; doi: https://doi.org/10.1101/2020.01.29.925685

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