Color vision is supported by retinal cone photoreceptors that, in most mammals, express two photopigments sensitive to short (S‐opsin) or middle (M‐opsin) wavelengths. Expression of the Opn1sw and Opn1mw genes, encoding S‐opsin and M‐opsin, respectively, is under the control of nuclear receptors, including thyroid hormone receptor β2 (TRβ2), retinoid X receptor γ (RXRγ), and RORβ, a member of the retinoic acid receptor‐related orphan receptor (ROR) family. We now demonstrate that RORα, another member of the ROR family, regulates Opn1sw, Opn1mw, as well as Arr3 (cone arrestin) in the mouse retina. RORα expression is detected in cones by postnatal day 3 and maintained through adulthood. The retinas of staggerer mice, carrying a null mutation of RORα, show significant down‐regulation of Opn1sw, Opn1mw, and Arr3. RORα acts in synergy with cone‐rod homeobox transcription factor (Crx), to activate the Opn1sw promoter in vitro. Chromatin immunoprecipitation assays reveal that RORα directly binds to the Opn1sw promoter, Opn1mw locus control region, and the Arr3 promoter in vivo. Our data suggest that RORα plays a crucial role in cone development by directly regulating multiple cone genes.
A weak, nonselective G protein-coupled receptor 120 (GPR120) agonist 10 was found by screening a series of carboxylic acids derived from the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist 3. Modification based on the homology model of GPR120 led to the first GPR120-selective agonist 12. These results provide a basis for constructing new tools for probing the biology of GPR120 and for developing new candidate therapeutic agents.
Distribution of the mt1 melatonin receptor in the guinea pig retina was immunocytochemically investigated using peptide-specific anti-mt1 receptor antibody. Western blots of the guinea pig retina showed a single band at approximately 37 kilodalton (kD) immunoreactive to the anti-mt1 antibody. The most intense immunoreactivity for the mt1 receptor was detected in the cell bodies of ganglion cells. Their dendrites and axons were also immunolabeled. Subpopulations of amacrine cells, the inner plexiform layer, and the outer plexiform layer also exhibited moderate to weak immunolabeling. The mt1-positive amacrine cells were located either at the vitreal border of the inner nuclear layer or displaced in the ganglion cell layer. Double immunolabeling using antibodies to the mt1 receptor and tyrosine hydroxylase revealed that the majority of dopaminergic amacrine cells showed mt1 immunoreactivity. Almost all the ICA type dopaminergic cells were mt1 positive while the 2CA type cells less frequently exhibited mt1 immunoreaction. By double immunolabeling for the mt1 receptor and GABA, more than 50% of the mt1-immunoreactive amacrine cells were shown to be GABAergic neurons. Approximately one-third of the GABAergic amacrine cells were immunolabeled for the mt1 receptor. The present results demonstrate expression of the mt1 receptor in diverse neuronal cell types in the guinea pig retina and provide the first evidence for the direct effect of melatonin on dopaminergic and GABAergic amacrine cells via the mt1 receptor.
ing of the apoptosis and clearance of neutrophils is limited The fate of neutrophils in the peripheral circulation by difficulties in studying their site-specific accumulation and is poorly understood. In this study, the role of Kupffer in quantifying their physiological cell death in the circulation. cells in eliminating aged and apoptotic neutrophils wasChromatin condensation and DNA fragmentation appear to investigated. Liver, spleen, lung, and blood samples from occur within a few minutes, 14 and the phagocytosis of apoWistar rats were examined by light and electron microsptotic neutrophils leads to their marked degradation, at copy, the terminal deoxynucleotidyl transferase-mediwhich point they are no longer recognizable as neutrophils. ated deoxyuridine triphosphate-biotin nick end labelThis rapidity of apoptosis and subsequent degradation may ing (TUNEL) method, and immunohistochemistry after explain the magnitude of these processes during the resoluthe intravenous injection of OK-432, a streptococcal tion of inflammation 15 and may not be reflected in microscopic preparation. Neutrophils were trapped predominantly observations of static histological sections. Furthermore, in the periportal and midzonal regions of hepatic lobules analysis of DNA fragmentation by gel electrophoresis cannot and were in contact with endothelial cells and Kupffer identify, localize, or quantify apoptosis at the cellular level. cells, or were surrounded by Kupffer cells. The trappingInvestigation of phagocytosis of apoptotic neutrophils in of neutrophils peaked after 6 hours. Apoptotic neutrothe circulation may lead to a greater understanding of the phils, with or without buds, were found in the lumen of physiological and pathological roles of the removal of circulathepatic sinusoids as early as 6 hours, reached maximal ing, senescent neutrophils. The increase in circulating levels after 12 hours, and represented greater than 60% neutrophils is one prerequisite for phagocytosis. The intraof the total number of neutrophils in the liver. The presperitoneal administration of inflammatory mediators, such ence of apoptotic neutrophils was correlated with the as OK-432 or lyophilized streptococcal bacteria, induces the degree of neutrophil phagocytosis. Double-staining accumulation of neutrophils in peritoneal exudates. 16 Intrashowed that TUNEL-positive neutrophils were phagocyvenous administration of these agents causes an inflammatosed or encircled by ED 1 -or ED 2 -positive Kupffer cells.tory reaction in the liver, as judged by the accumulation of In contrast, apoptosis and phagocytosis of neutrophils macrophages and leukocytes. 17,18 Clearly, mononuclear cell were rare in the spleen, lung, and peripheral blood.production must be exactly balanced by their loss to maintain These results suggested that the appearance of apohomeostasis. While a great deal is known about the accumuptotic neutrophils in the hepatic sinusoids and their lation of neutrophils in the liver, much less is understood rapid clearance by Kupffer cells occurs ...
Müller glia, the principal glial cell type in the retina, have the potential to reenter the cell cycle after retinal injury. In mammals, proliferation of Müller glia is followed by gliosis, but not regeneration of neurons. Retinal injury is also accompanied by phagocytic removal of degenerated cells. We here investigated the possibility that proliferation and gliosis of Müller glia and phagocytosis of degenerated cells may be regulated by the same molecular pathways. After N-methyl-N-nitrosourea-induced retinal injury, degenerated photoreceptors were eliminated prior to the infiltration of microglia/macrophages into the outer nuclear layer, almost in parallel with cell cycle reentry of Müller glia. Inhibition of microglia/macrophage activation with minocycline did not affect the photoreceptor clearance. Accumulation of lysosomes and rhodopsin-positive photoreceptor debris within the cytoplasm of Müller glia indicated that Müller glia phagocytosed most photoreceptor debris. Pharmacological inhibition of phosphatidylserine and Rac1, key regulators of the phagocytic pathway, prevented cell cycle reentry, migration, upregulation of glial fibrillary acidic protein, and phagocytic activity of Müller glia. These data provide evidence that phosphatidylserine and Rac1 may contribute to the crosstalk between different signaling pathways activated in Müller glia after injury.Müller glia, the principal glial cells in the retina, possess a variety of functions to support retinal neurons and act to maintain retinal homeostasis under physiological as well as pathological conditions 1,2 . In lower vertebrates like fish, retinal injury induces Müller glia to proliferate and dedifferentiate to neuronal progenitor cells that are capable of regenerating retinal neurons 3,4 . In mammals, however, such regenerative capacity of Müller glia is extremely limited. In rats, for example, Müller glia proliferate in response to injury, but they quickly exit the cell cycle and many undergo cell death possibly by DNA damage response 5 . In addition, Müller glia in mammals show a set of injury-induced responses called reactive gliosis, including cellular hypertrophy, migration, and upregulation of intermediate filaments such as glial fibrillary acidic protein (GFAP) and vimentin 6 . Although gliosis may be neuroprotective, it may hamper tissue repair if the reaction is prolonged 6 .Previous evidence has indicated that the injury-induced responses of Müller glia are mediated by growth factors or cytokines secreted from damaged neurons, microglia, or Müller glia themselves 6-8 . A pioneering study by Rattner and Nathans 9 showed that damaged photoreceptors produce endothelin2 (Edn2), which signals onto Müller glia and induces their reactive responses such as GFAP upregulation. However, the Edn2-mediated interaction between damaged photoreceptors and Müller glia seems to be initiated by Leukemia inhibitory factor (LIF) release from Müller glia 10 . Upregulation of LIF has been observed in a variety of retinal injury models 10-13 , and TNFα may be i...
Our findings suggest that the DNA damage response induced by unscheduled cell cycle reentry may be one of the mechanisms that limit the proliferative and regenerative capacity of Müller glia in the mammalian retina.
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