The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.
Bottom Line: This suggests that the Crb1(rd8/rd8) mutation is necessary, but not sufficient for the development of these degenerative features.By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified.This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
Affiliation: Department of Genetics and email@example.com.Show MeSH
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Mentions: The prominent degenerative changes in the inferior retina of some Crb1rd8/rd8 mice lead us to further investigate an association between photoreceptor death and Müller and microglia activation (Fig. 5). Prominent loss of DAPI positive signal on retinal flat mounts (Fig. 5A, B, Aii and Bii) and TUNEL+ photoreceptor nuclei in sections (Fig. 5E) are consistent with the darker labelling of photoreceptor nuclei (denser chromatin, pyknotic cell nuclei) and inner segments observed at the base of the whorls in semithin histology (e.g. Fig. 2A and C) and all together indicated loss of photoreceptors at the ONL in inbred Crb1rd8/rd8/J and C57BL/6 Crb1rd8/rd8 (2) mice. Without exception, these areas were closely associated with localized activation of microglia (Fig. 5Aiii and Biii) and Müller glia cell (Fig. 5Aiv, BiV, E and F). However, no significant differences in expression of chemokine (Ccl2, Ccr2, Cx3cl1 and Cx3cr1) or microglia activation marker (iNos, Arg1 or TGFb) were detected in retinas of different Crb1rd8/rd8 lines relative to wild type supporting a localized response of microglia cells to these degenerative events (Supplementary Material, Fig. S2). In all these assessments, C57BL/6 Crb1rd8/rd8 (1) animals appeared similar to wild-type mice with the exception of the rare appearance of subtle aneurysm-like changes at the OPL (Fig. 5C, Ci–iV and G). Three-dimensional (3D) reconstruction of large inferior lesions revealed how activated Müller and microglia cells surround several photoreceptor columns at the OPL (Fig. 5I) and contribute to the formation of gliotic scars at the OLM (Fig. 5J). These processes separate photoreceptor nuclei that have lost their orderly arrangement within the ONL from still normally packed and healthy photoreceptors in their close vicinity (Fig. 5K and L).Figure 5.