Purinergic signaling mediated by P2X₇ receptors controls myelination in sciatic nerves

Abstract

Adenosine-5'-triphosphate, the physiological ligand of P2X receptors, is an important factor in peripheral nerve development. P2X7 receptor is expressed in Schwann cells (SCs), but the specific effects of P2X7 purinergic signaling on peripheral nerve development, myelination, and function are largely unknown. In this study, sciatic nerves from P2X7 knockout mice were analyzed for altered expression of myelin-associated proteins and for alterations in nerve morphology. Immunohistochemical analyses revealed that, in the wild-type peripheral nerves, the P2X7 receptor was localized mainly in myelinating SCs, with only a few immunopositive nonmyelinating SCs. Complete absence of P2X7 receptor protein was confirmed in the sciatic nerves of the knockout mice by Western blot and immunohistochemistry. Western blot analysis revealed that expression levels of the myelin proteins protein zero and myelin-associated glycoprotein are reduced in P2X7 knockout nerves. In accordance with the molecular results, transmission electron microscopy analyses revealed that P2X7 knockout nerves possess significantly more unmyelinated axons, contained in a higher number of Remak bundles. The myelinating/nonmyelinating SC ratio was also decreased in knockout mice, and we found a significantly increased number of irregular fibers compared with control nerves. Nevertheless, the myelin thickness in the knockout was unaltered, suggesting a stronger role for P2X7 in determining SC maturation than in myelin formation. In conclusion, we present morphological and molecular evidence of the importance of P2X7 signaling in peripheral nerve maturation and in determining SC commitment to a myelinating phenotype.

Up-regulation of P2X7 receptors mediating proliferation of Schwann cells after sciatic nerve injury

“…Previous studies have presented evidence that P2X7R are expressed in the paranodal membrane of rat Schwann cells in vivo [15], in cultured mouse Schwann cells [8,21,24], in longitudinal sciatic nerve sections of rat and mouse [20] and in cross and longitudinal sciatic nerve sections of mouse [12]. In this study, we clearly demonstrate localization of P2X7R ir in two types of Schwann cells in longitudinal sciatic nerve sections.…”

“…With methods of patch-clamp recording, fluorescent dye uptake and immunocytochemistry, P2X7R were detected in cultured mouse Schwann cells [8]. Recent data has shown that P2X7R control myelination in sciatic nerves and contribute to the death of Schwann cells transplanted into the spinal cord [12,20].…”

Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis

“…P2X7R could also regulate extracellular K+ homeostasis and participate to the removal of excess glutamate, by directly modulating K+ efflux ( 64 , 65 ). Moreover, increased P2X7R might influence the connectivity of neuronal circuits, being the receptor known to be involved in the control of myelination ( 29 ), or provide metabolic support to neurons, by regulating the lipid metabolism pathway ( 66 ). Finally, P2X7R might participate to preserve the blood–brain barrier ( 60 ), since we demonstrated here its expression in astrocytes protruding their vascular feet on external capillary walls.…”

“…A member of the purinergic P2X family of ATP-gated ion channels, the P2X7 receptor (P2X7R) ( 15 ) is selectively expressed on cells of the hematopoietic lineage ( 16 – 19 ). Moreover, in the nervous system, P2X7R is present on activated microglia ( 20 – 22 ), astrocytes ( 23 – 25 ), oligodendrocytes ( 26 – 28 ), Schwann cells ( 29 ), and neurons ( 30 ). Despite its wide expression in many cell types participating to MS, only incomplete information is available regarding P2X7-mediated signaling in the disease.…”

How Schwann Cells Sort Axons

“…The radial sorting of axons coincides with the onset of active spontaneous low frequency impulse activity in peripheral neurons (Fitzgerald, 1987) and this activity induces ionic imbalances and neurotransmitter secretion that affect immature Schwann cell proliferation and differentiation in-vitro (Stevens and Fields, 2000; Stevens and others, 2004). Indeed, two Schwann cell neurotransmitter receptors, the purinergic receptor P2X 7 , and the GABA-B1 G protein receptor, have shown to be necessary for the formation of Remak bundles (Faroni and others, 2014a; Faroni and others, 2014b). While the localization of these receptors at the axoglial interface remains to be proven, they might represent good candidates to regulate axonal recognition during radial sorting.…”