Search

Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors. [ABSTRACT FROM AUTHOR]

There is an ongoing controversy regarding the role of WDR36 sequence variants in the pathogenesis of primary open-angle glaucoma (POAG). WDR36 is a nucleolar protein involved in the maturation of 18S rRNA. The function of WDR36 is essential as homozygous Wdr36 -deficient mouse embryos die before reaching the blastocyst stage. Here we provide a detailed analysis of the phenotype of heterozygous Wdr36 -deficient mice. Loss of one Wdr36 allele causes a substantial reduction in the expression of Wdr36 mRNA. In the eyes of Wdr36 +/− animals, the structure of the tissues involved in aqueous humor circulation and of the optic nerve head are not different from that of control littermates. In addition, one-year-old Wdr36 +/− animals do not differ from wild-type animals with regards to intraocular pressure and number of optic nerve axons. The susceptibility of retinal ganglion cells to excitotoxic damage induced by NMDA is similar in Wdr36 +/− and wild-type animals. Moreover, the amount of optic nerve axonal damage induced by high IOP is not different between Wdr36 +/− and wild-type mice. Transgenic overexpression of mutated Del605-607 Wdr36 in Wdr36 +/− animals does not cause changes in the number of optic nerve axons or susceptibility to excitotoxic damage. In addition, analysis of 18S rRNA maturation in Del605-607 Wdr36 +/− or Wdr36 +/− mice does not show obvious differences in rRNA processing or in the amounts of precursor forms when compared to wild-type animals. Our data obtained in Wdr36 +/− mice do not support the assumption of a causative role for WDR36 in the pathogenesis of POAG. [ABSTRACT FROM AUTHOR]

Mutations in the myocilin gene (MYOC) are causative for 10% of cases with juvenile open-angle glaucoma and 3-4% of those with primary open-angle glaucoma. Myocilin is a secreted protein with relatively ill-defined matricellular properties. Despite its high expression in the eye, myocilin-deficient mice have originally been reported to have no obvious ocular phenotype. Here we revisited the ocular phenotype of myocilin-deficient mice and detected a higher number of neurons in their inner (INL) and outer (ONL) nuclear layers, as well as a higher number of retinal ganglion cells (RGC) and their axons. The increase in retinal neurons appears to be caused by a decrease in programmed developmental cell death, as apoptosis of retinal neurons between postnatal days 4 and 10 was found to be attenuated when compared to that of wildtype littermates. In contrast, when Myoc-/- mice were crossed with βB1-crystallin-MYOC mice with ectopic overexpression of myocilin in the eye, no differences in developmental apoptosis, RGC number and INL thickness were observed when compared to wildtype littermates. The amounts of the anti-apoptotic Bcl-2-like protein 1 (BCL2L1, Bcl-xL) and its mRNA were increased in retinae of Myoc-/- mice, while lower amounts of BCL2L1 and its mRNA were detected in mixed Myoc-/-/βB1-crystallin-MYOC mice. The structural differences between Myoc-/- mice and wildtype littermates did not result in functional differences as measured by electroretinography. Noteworthy though mixed Myoc-/-/βB1-crystallin-MYOC mice with ocular overexpression of myocilin had significant cone function deficits. Myocilin appears to modulate apoptotic death of retinal neurons likely by interacting with the intrinsic apoptotic pathway. [ABSTRACT FROM AUTHOR]