Nectin-like 4 (Necl4, Cadm4) is a Schwann cell-specific cell adhesion molecule that promotes axo-glial interactions. In vitro and in vivo studies have shown that Necl4 is necessary for proper peripheral nerve myelination. However the molecular mechanisms that are regulated by Necl4 and affect peripheral myelination currently remain unclear. We used an in vitro approach to start identifying some of the mechanisms that could explain Necl4 function. Using mass spectrometry and Western blot techniques, we have identified Choline Transporter-Like 1 (CTL1) as a putative complexing partner with Necl4. We show that intracellular choline levels are significantly elevated in Necl4-deficient Schwann cells. The analysis of extracellular d9-choline uptake revealed a deficit in the amount of d9-choline found inside Necl4-deficient Schwann cells, suggestive of either reduced transport capabilities or increased metabolization of transported choline. An extensive lipidomic screen of choline derivatives showed that total phosphatidylcholine and phosphatidylinositol (but not diacylglycerol or sphingomyelin) are significantly elevated in Necl4-deficient Schwann cells, particularly specific subspecies of phosphatidylcholine carrying very long polyunsaturaed fatty acid chains. Finally, CTL1-deficient Schwann cells are significantly impaired in their ability to myelinate neurites in vitro. To our knowledge, this is the first demonstration of a bona fide cell adhesion molecule, Necl4, regulating choline homeostasis and lipid biogenesis. Phosphatidylcholines are major myelin phospholipids, and several phosphorylated phosphatidylinositols species are known to regulate key aspects of peripheral myelination. Furthermore the biophysical properties imparted to plasma membranes are regulated by fatty acid chain profiles. It will be therefore important to translate these in vitro observations to in vivo studies of Necl4 and CTL1-deficient mice.
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