Expression of a catalytically inactive transmembrane protein tyrosine phosphatase ϵ (tm-PTPϵ) delays optic nerve myelination
✍ Scribed by Naser Muja; Gabor Lovas; Elena Romm; Dietrich Machleder; Mukul Ranjan; Vittorio Gallo; Lynn D. Hudson
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 934 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0894-1491
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✦ Synopsis
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 ϵ (PTPϵ) in oligodendrocytes, we applied a substrate‐trapping approach in the development of transgenic mice overexpressing a catalytically inactive, transmembrane PTPϵ‐hemaglutinin (tm‐PTPϵ‐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, α‐enolase and β‐actin, were phosphorylated to a greater degree in transgenic mice. Despite a high degree of tm‐PTPϵ‐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‐PTPϵ‐HA is simultaneously expressed in myelin‐forming glia and their neuronal targets. While tm‐PTPϵ related signaling pathways may figure in axon‐glial interactions, interfering with tm‐PTPϵ activity does not perceptibly affect the development or myelinating capacity of most oligodendrocytes. © 2004 Wiley‐Liss, Inc.