Transgenic mice exhibiting oligodendrocyte‐specific expression of a mutant protein tyrosine phosphatase epsilon

Abstract

Reversible tyrosine phosphorylation is integral to oligodendrocyte differentiation, and one participant of the phosphorylation cycle, PTPε, is induced in developing oligodendrocytes (Ranjan and Hudson, 1996). To define the role of PTPε, we generated mice expressing a catalytically inactive, hemagglutinin‐epitope tagged PTPε (HA‐PTP ε) from the 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase (CNP) promoter. By competing with endogenous, normal PTPε for substrate binding, HA‐PTPε would behave in a dominant negative fashion when overexpressed in these mice. Transgene mRNA peaks at postnatal day 21, coincident with the maximal expression of myelin protein mRNAs. Immunohistochemical analyses using antibodies against the HA epitope tag demonstrate that HA‐PTPε is expressed in oligodendrocytes, but not in astrocytes and neurons. HA immunoreactivity was present in all myelinated brain structures including the corpus callosum, anterior commissure, and fornix, as well as in the subcortical, cerebellar, and spinal cord white matter. Gross differences in myelination or oligodendrocyte cell density in these brain regions were not detected using antibodies against CNP, myelin basic protein, and an oligodendrocyte marker, CC1. However, by EM axons of the optic nerve appear smaller and less extensively myelinated in transgenic mice than in wild‐type littermates. Studies are underway to determine the functional effects of transgene expression on conduction velocity, on the profile of expressed genes, and on potential phosphorylated protein targets of PTPε.