Protein tyrosine phosphatase Meg2 deficient mice - A powerful model to study glaucoma disease?

Abstract

Purpose: Dephosphorylation of proteins on tyrosine residues via members of the protein tyrosine phosphatase (PTP) superfamily is a critical factor for the outcome of numerous diseases, including cancer or diabetes. Moreover, PTP members represent crucial signaling molecules in the regulation of the immune response. In a previous study we described the dramatic retinal/eye phenotype of embryonic and early postnatal (P0) PTP-Meg2 knockout (KO) mice (Wang et al., 2005; ARVO 2012; in progress). In order to investigate the consequence of PTP-Meg2 loss in more detail, we performed retinal microarray analyses in P0 PTP-Meg2 KO mutants and wildtype (WT) control littermates. Surprisingly, based on this approach, we verified a dysregulation of several candidate genes highly associated with intraocular pressure (IOP) elevation, a hallmark of glaucoma disease. In the present consecutive study we investigated the potential “glaucoma phenotype” of adolescent PTP-Meg2 heterozygous (HET) mice.

Methods: Tonometry analysis was used to evaluate IOP in PTP-Meg2 HET and WT animals. Immunohistochemistry, electron microscopy, protein biochemical analyses as well as photopic electroretinogram (ERG) recordings were used to characterize adult PTP-Meg2 deficient mice.

Results: As verified by tonometry analysis, PTP-Meg2 HET mice develop a progressive IOP elevation during late adolescence. At one year of age, PTP-Meg2 HET animals exhibit a visible “glaucoma phenotype“ accompanied by a dramatic loss of retinal ganglion cells and optic nerve degeneration. Finally, ERG recordings revealed that PTP-Meg2 HET mice exhibit reduced a- and b-wave amplitudes and implicit time prolongation, suggesting a progressive retinal damage.

Conclusions: In conclusion, PTP-Meg2 deficient mice may serve as a new powerful animal model to study the pathomechanisms involved in onset and progression of glaucoma disease. To our knowledge, this is the first report of a “glaucoma phenotype” in a PTP deficient animal.

Keywords: 740 transgenics/knock-outs • 535 gene microarray • 568 intraocular pressure