A hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal degeneration, however, is unclear. This study assessed this by examining Müller cell dysfunction via glutamine synthetase immunoreactivity and its spatial association with retinal neuron subpopulations through various cell markers.
Aged Rd1 mice retinae (P150 - P536, n = minimum 5 per age) and control heterozygous rd1 mice retinae (P536, n = 5) were isolated, fixed and cryosectioned. Fluorescent immunolabeling of glutamine synthetase was performed and retinal areas quantified as having low glutamine synthetase immunoreactivity if proportion of labeled pixels in an area was less than two standard deviations of the mean of the total retina. Other Müller cell markers such as Sox9 and Glial fibrillary acidic protein along with neuronal cell markers Calbindin, Calretinin, recoverin, Protein kinase C-α, Glutamic acid decarboxylase 67, and Islet-1 were then quantified within areas of low and normal synthetase immunoreactivity.
Glutamine synthetase immunoreactivity was lost as a function of age in the rd1 mouse retina (P150 - P536). Immunoreactivity of other Müller cell markers, however, were unaffected suggesting Müller cells were still present in these low glutamine synthetase immunoreactive regions. Glutamine synthetase immunoreactivity loss affected specific neuronal populations: Type 2, Type 8 cone, and rod bipolar cells, as well as AII amacrine cells based on reduced recoverin, protein kinase Ca and parvalbumin immunoreactivity, respectively. The number of cell nuclei within regions of low glutamine synthetase immunoreactivity was also reduced suggesting possible neuronal loss rather than reduced cell marker immunoreactivity.
These findings further support a strong interplay between glia-neuronal alterations in late-stage degeneration and highlight a need for future studies and consideration in intervention development.
Copyright © 2023 Reynisson, Kalloniatis, Fletcher, Shivdasani and Nivison-Smith.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) which ultimately forms plaques. These Aβ deposits can be induced in APP transgenic mouse models by prion-like seeding. It has been widely accepted that anosmia and hyposmia occur during the early stages of AD, even before cognitive deficits are present. In order to determine the impact of seed-induced Aβ deposits on olfaction, we performed intracerebral injections of seed-competent brain homogenate into the olfactory bulb of young pre-depositing APP transgenic mice. Remarkably, we observed a dramatic olfactory impairment in those mice. Furthermore, the number of newborn neurons as well as the activity of cells in the mitral cell layer was decreased. Notably, exposure to an enriched environment reduced Aβ seeding, vivified neurogenesis and most importantly reversed olfactory deficits. Based on our findings, we conclude that altered neuronal function as a result of induced Aβ pathology might contribute to olfactory dysfunction in AD.
© 2022. The Author(s).

Intraocular medulloepithelioma (IO-MEPL) is a rare embryonal ocular neoplasm, prevalently occurring in children. IO-MEPLs share histomorphological features with CNS embryonal tumors with multilayered rosettes (ETMRs), referred to as intracranial medulloepitheliomas. While Sonic hedgehog (SHH) and WNT signaling pathways are crucial for ETMR pathogenesis, the impact of these pathways on human IO-MEPL development is unclear. Gene expression analyses of human embryonal tumor samples revealed similar gene expression patterns and significant overrepresentation of SHH and WNT target genes in both IO-MEPL and ETMR. In order to unravel the function of Shh and Wnt signaling for IO-MEPL pathogenesis in vivo, both pathways were activated in retinal precursor cells in a time point specific manner. Shh and Wnt co-activation in early Sox2- or Rax-expressing precursor cells resulted in infiltrative ocular lesions that displayed extraretinal expansion. Histomorphological, immunohistochemical, and molecular features showed a strong concordance with human IO-MEPL. We demonstrate a relevant role of WNT and SHH signaling in IO-MEPL and report the first mouse model to generate tumor-like lesions with features of IO-MEPL. The presented data may be fundamental for comprehending IO-MEPL initiation and developing targeted therapeutic approaches.
© 2021. The Author(s).

The objective of this study was to map the distribution and density of the three major components of the classical scotopic "night vision" pathway (rods, rod bipolar, and AII amacrine cells) in postmortem human retinas.
Four postmortem donor eyes (male and female, aged 44-56 years) were used to cut vertical sections through the temporal horizontal meridian. The sections were processed for immunohistochemistry and imaged using high-resolution multichannel confocal microscopy. Rods, rod bipolar, and AII amacrine cells were counted along the temporal horizontal meridian. Two additional retinas were used for intracellular injections.
Rod peak density is close to 150,000 cells/mm2 at 4 to 5 mm (15° to 20°) eccentricity, declining to below 70,000 cells/mm2 in peripheral retina. Rod bipolar density is lower but follows a similar distribution with peak density near 10,000 cells/mm2 between 2 and 4 mm (7° to 15°) eccentricity declining to below 4000 cells/mm2 in peripheral retina. The peak density of AII amacrine cells (near 4000 cells/mm2) is located close to the fovea, at 0.5- to 2 mm-eccentricity (2° to 7°) and declines to below 1000 cells/mm2 in the periphery. Thus, convergence between rods and AII cells increases from central to peripheral retina.
Comparison with human psychophysics and ganglion cell density indicates that the spatial resolution of scotopic vision is limited by the AII mosaic at eccentricities below 15° and by the midget ganglion cell mosaic at eccentricities above 15°.

Pleural fibrosis is defined as excessive depositions of matrix components that result in pleural tissue architecture destruction and dysfunction. In severe cases, the progression of pleural fibrosis leads to lung entrapment, resulting in dyspnea and respiratory failure. However, the mechanism of pleural fibrosis is poorly understood.
miR-4739 levels were detected by miRNA array and real-time PCR. Real-time PCR, western blotting and immunofluorescence were used to identify the expression profile of indicators related to fibrosis. Target gene of miR-4739 and promoter activity assay was measured by using dual-luciferase reporter assay system. In vivo, pleural fibrosis was evaluated by Masson staining and miR-4739 level was detected by In situ hybridization histochemistry.
We found that bleomycin induced up-regulation of miR-4739 in pleural mesothelial cells (PMCs). Over-regulated miR-4739 mediated mesothelial-mesenchymal transition and increased collagen-I synthesis in PMCs. Investigation on the clinical specimens revealed that high levels of miR-4739 and low levels of bone morphogenetic protein 7 (BMP-7) associated with pleural fibrosis in patients. Then we next identified that miR-4739 targeted and down-regulated BMP-7 which further resulted in unbalance between Smad1/5/9 and Smad2/3 signaling. Lastly, in vivo studies revealed that miR-4739 over-expression induced pleural fibrosis, and exogenous BMP-7 prevented pleural fibrosis in mice.
Our data indicated that miR-4739 targets BMP-7 which mediates pleural fibrosis. The miR-4739/BMP-7 axis is a promising therapeutic target for the disease. FUND: The National Natural Science Foundation of China.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.