Expression of a catalytically inactive transmembrane protein tyrosine phosphatase ϵ (tm‐PTPϵ) delays optic nerve myelination

Abstract

Reversible tyrosine phosphorylation is integral to the process of oligodendrocyte differentiation. To interfere with the subset of the phosphorylation cycle overseen by protein tyrosine phosphatase epsilon (PTP epsilon) in oligodendrocytes, we applied a substrate-trapping approach in the development of transgenic mice overexpressing a catalytically inactive, transmembrane PTP epsilon-hemaglutinin (tm-PTP epsilon-HA) from the dual promoter element of the gene encoding the myelin protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Transgene expression peaked during the active myelinating period, at 2-3 weeks postnatal. Two tyrosine phosphoproteins, alpha-enolase and beta-actin, were phosphorylated to a greater degree in transgenic mice. Despite a high degree of tm-PTP epsilon-HA expression, myelin was grossly normal in nearly all axonal tracts. Phenotypic abnormalities were limited to optic nerve, where a decrease in the degree of myelination was reflected by reduced levels of myelin proteins on postnatal day 21 (PND21), as well as a decrease in the density of differentiated oligodendrocytes. The optic chiasm was reduced in thickness in transgenic mice; optic nerves similarly exhibited a reduction in transverse width. Further analyses of the optic pathway demonstrated that transgenic protein was unexpectedly present in retinal ganglion cells, whose axons are the targets of myelination by optic nerve oligodendrocytes. On PND28, transgenic protein declined dramatically in both oligodendrocytes and retinal ganglion cells contributing to the recovery of optic nerve myelination. Thus, delayed myelination arises only when tm-PTP epsilon-HA is simultaneously expressed in myelin-forming glia and their neuronal targets. While tm-PTP epsilon related signaling pathways may figure in axon-glial interactions, interfering with tm-PTP epsilon activity does not perceptibly affect the development or myelinating capacity of most oligodendrocytes.

Protein tyrosine phosphatase epsilon and Neu-induced mammary tumorigenesis

“…Furthermore, this latter effect correlates with reduced function of Schwann cells in vivo as mice lacking PTPɛ suffer from a severe but transient delay in sciatic nerve myelination [58]. Expression of an inactive, "substrate-trapping" mutant of the receptor form of this phosphatase, RPTPɛ, also causes delayed optic nerve myelination in transgenic mice [59]. A second function of cyt-PTPɛ is to support the boneresorbing function of osteoclasts.…”

Association of Tyrosine Phosphatase Epsilon with Microtubules Inhibits Phosphatase Activity and Is Regulated by the Epidermal Growth Factor Receptor

“…cyt-PTPε is important for proper adhesion of osteoclasts to bone (7) and dephosphorylates and downregulates delayed-rectifier voltage-gated potassium channels in Schwann cells, thereby countering their activation by c-Src and c-Fyn. This effect correlates in vivo with delayed myelination of sciatic nerve axons in young PTPε-deficient mice (33,40,41) and with delayed optic nerve myelination in mice expressing a "substrate-trapping" mutant of RPTPε (29). cyt-PTPε can also downregulate signaling mediated by the mitogen-activated protein kinase (42,45) and JAK-STAT (37-39) pathways and is required for proper functioning of mouse macrophages (35).…”

Inhibitors of myelination: ECM changes, CSPGs and PTPs

“…PTPε, on the other hand, appears to promote oligodendrocyte differentiation and myelination. While most CNS myelin tracts are normal in mice expressing an inactive form of PTPε, there are lower numbers of differentiated oligodendrocytes and delayed myelination of the optic nerve (Muja et al, 2004). However, since transgene expression also occurs in the retinal ganglion cells whose axons were abnormally myelinated, disruption of PTPε signaling occurred in both cell types, complicating interpretation.…”