Phosphatidylinositol 4-kinase type IIIα (PI4KA) is required for proper myelination of peripheral nerves in mice

Authors

• A Alvarez-Prats
• I Bjelobaba
• K Yeun Ju
• D Abebe
• T Balla

Abstract

Myelination of axons is essential for proper neuronal signal propagation. Our recent studies identified phosphatidylinositol 4-kinase III-alpha (PI4KA) as a key regulator of phosphatidylserine (PS) metabolism in mammalian cells. Since PS and phosphatidylethanolamine (PE) are key components of the myelin sheath, we decided to evaluate the role of this kinase in myelination using a mouse model. We created Schwann cell-specific PI4KA knockout mice by crossing mice that have floxed alleles of pi4ka with a line that expresses Cre recombinase controlled by the myelin protein zero (P0) (MPZ) promoter. Three groups of mice were generated: Pi4ka(fl/fl)Cre+, Pi4ka(fl/wt)Cre+, and Pi4ka(wt/wt)Cre+, the latter two groups serving as controls. Here, we demonstrate that PI4KA is required by Schwann cells to properly myelinate the murine peripheral nervous system (PNS). Histological and DNA analysis of collected tissues were performed using H&E staining and genomic PCR, respectively. Protein expression was detected by western blot (WB) and Immunohistochemistry (IHC). The gait behavior was analyzed using the TreadScanTM system, an instrument that takes video of the animal, and determine various characteristic parameters related to possible pathophysiological conditions. Electron Microscopy (EM) analysis was performed on the sciatic nerves, and also lipidomic analysis, to study their lipid profile. We conclude that genetic ablation of PI4KA causes defects in myelination during development in mice. To elucidate the underlying cause of the myelination problem, we will analyze the lipid profile, signal transduction pathways and migrational response of Schwann cells after pharmacological inhibition of PI4KA.

Scientific Focus Area: Neuroscience

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