An RCS-Like Retinal Dystrophy Phenotype in<i>Mer</i>Knockout Mice

Duncan, Jacque L.; LaVail, Matthew M.; Yasumura, Douglas; Matthes, Michael T.; Yang, Hongbo; Trautmann, Nikolaus; Chappelow, Aimee V.; Feng, Wei; Earp, H. Shelton; Matsushima, Glenn K.; Vollrath, Douglas

doi:10.1167/iovs.02-0438

Cited by 226 publications

(264 citation statements)

References 72 publications

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“…Moreover, the RPE of these mice failed to display any AF changes, clearly indicating that A2E is not the primary initiator of light-induced retinal degeneration in this mouse model. However, Mertk-deficient mice did reveal infiltration of microglia/macrophages into the subretinal space (42,52), indicating that these cells likely contribute to the clearance of photoreceptor cell debris.…”

Section: Discussionmentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

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Section: Discussionmentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…As noted above, degeneration of photoreceptors was originally noted in mice lacking all three TAM receptors 20 . However, this was subsequently found -in rats, mice and humans -to be due to mutations of the Mer gene alone [37][38][39][40][41] . A long-studied inherited form of retinitis pigmentosa in rats [37][38][39] , and a more recently described inherited form of the disease in humans 40,41 , are both due to Mer gene mutations.…”

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

“…However, this was subsequently found -in rats, mice and humans -to be due to mutations of the Mer gene alone [37][38][39][40][41] . A long-studied inherited form of retinitis pigmentosa in rats [37][38][39] , and a more recently described inherited form of the disease in humans 40,41 , are both due to Mer gene mutations. MER and TYRO3 have been localized to the apical tips of the RPE cell processes that penetrate the photoreceptor outer segment layer and pinch off the distal ends of the outer segments 10 .…”

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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“…• Défaut de la phagocytose des photorécepteurs, dégénérescence rétinienne [16,20,21] Tableau III. Phénotypes associés à l'invalidation génique des récepteurs TAM chez la souris et à la mutation nulle du récepteur Mer chez le rat RCS.…”

Section: Système Visuelunclassified

“…Les études de clonage positionnel menées chez le rat RCS ont permis de lier cette dégénérescence rétinienne à une mutation nulle du gène Mer [20]. En outre, l'invalidation du gène Mer chez la souris entraîne un phénotype dystrophique similaire à celui des rats RCS [21]. En accord avec ces observations, l'invalidation des 3 gènes codant pour les récepteurs TAM chez la souris conduit à une cécité postnatale consécutive à des dégénérescences des photorécepteurs (Tableau III) [16].…”

Section: Système Visuelunclassified