Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

Abstract

Progranulin (PGRN) is a secreted glycoprotein that regulates numerous cellular processes. The role of PGRN as a regulator of lysosomes has recently received attention. The purpose of this study was to characterize the retinal phenotype in mature PGRN knockout (Grn−/−) mice. The a-wave amplitude of scotopic electroretinogram and outer nuclear thickness were significantly reduced at 6 months of age in Grn−/− mice compared to wild-type (Grn+/+) mice. In Grn−/− mice, retinal microglial cells accumulated on the retinal pigment epithelium (RPE) apical layer, and the number of infiltrated microglia and white fundus lesions between 2 and 6 months of age showed a close affinity. In Grn+/+ mice, PGRN was located in the retina, while the strongest PGRN signals were detected in the RPE-choroid. The different effects of PGRN deficiency on the expression of lysosomal proteins between the retina and RPE-choroid were demonstrated. Our data suggest that the subretinal translocation of microglia is a characteristic phenotype in the retina of mature PGRN knockout mice. The different effects of PGRN deficiency on the expression of lysosomal proteins between the retina and RPE-choroid might modulate microglial dynamics in PGRN knockout mice.

Progranulin Insufficiency Affects Lysosomal Homeostasis in Retinal Pigment Epithelium

“…However, in the current study, transient progranulin knockdown did not affect the expression level of lysosome proteins in RPE cells (Figure 3). Consistent with the results of the current study, the expression of lysosomal proteins in the RPE-choroid complex was not affected in PGRN knockout mouse (34). Lysosomal dysfunction may result from dysregulation of any of the myriad of proteins required for maintaining lysosomal homeostasis.…”

“…In addition, progranulin directly or indirectly binds to trafficking receptors, sortilin, or cation-independent mannose 6-phosphate receptor (CI-M6PR) and is carried to the lysosome (8,30). In the retinal cross section of wild-type mice, high levels of progranulin expression were observed in the RPE layer as well as in the neuronal retina (24,34). However, there was no evidence of the intracellular localization and function of progranulin in RPE cells.…”

Single-Cell Transcriptomics Reveals Cellular Heterogeneity and Complex Cell–Cell Communication Networks in the Mouse Cornea

“…CEnC II contributed more as TGF-β sources than the CEnC I cluster, consistent with the scRNA-seq finding that CEnC II expresses more EnMT-related genes. Although the exact nature of the newly discovered Pros, Grn and visfatin signaling pathways in cornea remains unclear, it has been observed that these three signaling pathways were associated with retina, including that Pros1 mutation correlates with inherited retinal degenerations, 58 Grn deficiency results in photoreceptor degeneration in mouse retina 59 and visfatin expression in diabetic rat retina. 60 Although chemerin has been shown to promote vessel growth in the mouse corneal angiogenesis model, 61 its specific role in the cornea remains unexplored.…”