Differential expression of protein tyrosine phosphatases in canine models of retinal degeneration

Abstract

Purpose : Protein tyrosine phosphatases (PTPs) are enzymes critical for the regulation of signaling networks that drive cell differentiation, proliferation and survival. Dysregulation of phosphotyrosine-dependent events has been associated with pathogenesis of cancer, neurocognitive disorders, and retinal degeneration (RD). For instance, in mice, the loss of functional PTEN, PTPN6, or PTPN11 has been implicated in RD. In this study, we explore the PTP transcriptome landscape of the canine retina in health and disease and examine PTPs expression profiles in naturally occurring canine models of inherited RD.

Methods : The expression profile of PTP genes in the adult human retina was determined in silico using the RETINAL Transcriptome track (UCSC Genome Browser), and orthologs of human PTP genes were identified using RNA-Seq data from the WT canine retina (age: 24 wks; n=3). To assess potential involvement of the PTP gene family in the pathogenesis of hereditary RD in dogs, retinal transcriptomes from two canine mutant retinas, rcd1 and xlpra2 (n=3 each group), at clinically relevant advanced disease stages (ages: 22 wks, and 41 wks, respectively) (Sudharsan et al., 2017) were examined in comparison to the WT RNA-Seq dataset.

Results : PTP genes were found to be widely expressed in both the canine as well as human retina. Out of 125 PTP genes recognized in the human genome, 118 transcripts were identified in the adult human retina, and a comparable number of PTP orthologs (105) was detected in the canine retina. RNA-Seq data analysis revealed 69 significantly dysregulated PTPs in rcd1 mutant and 53 differentially expressed PTP transcripts in xlpra2 retina vs WT (≥ 2 FC, p < 0.05), with a significant overlap of 51 misregulated PTPs shared between the two mutant models. qRT-PCR validation of the most upregulated (PTPRC, PTPRS, PTPN14) and downregulated (PTPRU, PTPN21, PTPN22) genes is currently in progress along with evaluation of other canine RD models (RPE65, prcd, cBest) at early and advanced disease stages.

Conclusions : PTP genes are widely expressed in the human and canine retina, with 100+ PTP orthologs shared between the two species, suggesting similar mechanisms controlling retinal homeostasis. The overlapping pattern of PTP dysregulation in canine rcd1- and xlpra2- RD models strongly indicates the presence of common pathways underlying cellular responses in the RD-mutant retinas.

This is a 2020 ARVO Annual Meeting abstract.