The Role of Rab27a in the Regulation of Melanosome Distribution within Retinal Pigment Epithelial Cells

Futter, Clare E.; Ramalho, José S.; Jaissle, Gesine B.; Seeliger, Mathias W.; Seabra, Miguel C.

doi:10.1091/mbc.e03-10-0772

Cited by 95 publications

(119 citation statements)

References 37 publications

(36 reference statements)

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“…7,9,41 Most of the MYO7A in the RPE is associated with melanosomes. 10,11,19 Quantitative studies have shown that this proportion (70-80%) is similar among mouse, pig and human RPE. 11 A major focus of the present study was on RPE cell correction, especially the role of MYO7A in melanosome motility and localization, for which we have the most tractable assays.…”

Section: Lv-myo7a Expression and Correction Of Cellular Events In Phomentioning

confidence: 96%

“…In the shaker1 RPE, the localization and motility of both phagosomes and melanosomes are defective, suggesting roles for MYO7A in the transport of these organelles. 11,[17][18][19] The phagosomes result from the phagocytosis of the photoreceptor outer segment tips, as part of the renewal of the photoreceptor disk membranes, 20 a critical process for the viability of photoreceptor cells. 21 The role of melanosomes in the RPE is not well defined, however, their functions include light absorption, possibly a contribution to the digestion of phagosomes, and protection against lipid peroxidation and the formation of toxic oxiranes from ingested photoreceptor outer segment phospholipids.…”

Section: Introductionmentioning

confidence: 99%

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Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

Hashimoto¹,

et al. 2007

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One of the most disabling forms of retinal degeneration occurs in Usher syndrome, since it affects patients who already suffer from deafness. Mutations in the myosin VIIa gene (MYO7A) cause a major subtype of Usher syndrome, type 1B. Owing to the loss of function nature of Usher 1B and the relatively large size of MYO7A, we investigated a lentiviral-based gene replacement therapy in the retinas of MYO7A-null mice. Among the different promoters tested, a CMV-MYO7A chimeric promoter produced wild-type levels of MYO7A in cultured RPE cells and retinas in vivo. Efficacy of the lentiviral therapy was tested by using cell-based assays to analyze the correction of previously defined, MYO7A-null phenotypes in the mouse retina. In vitro, defects in phagosome digestion and melanosome motility were rescued in primary cultures of RPE cells. In vivo, the normal apical location of melanosomes in RPE cells was restored, and the abnormal accumulation of opsin in the photoreceptor connecting cilium was corrected. These results demonstrate that a lentiviral vector can accommodate a large cDNA, such as MYO7A, and mediate correction of important cellular functions in the retina, a major site affected in the Usher syndrome. Therefore, a lentiviral-mediated gene replacement strategy for Usher 1B therapy in the retina appears feasible.

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Section: Lv-myo7a Expression and Correction Of Cellular Events In Phomentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

Hashimoto¹,

et al. 2007

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“…Rab27A is one of two isoforms of the Rab27 subfamily -the other being Rab27B. Mice deficient for Rab27A exhibit defects in intracellular migration of melanosomes along the actin filaments (Futter et al, 2004) producing a phenotypic coat color referred to as ashen. The equivalent mutation in humans results in hypopigmentation that copresents with a severe immune disorder, collectively referred to as Griscelli syndrome 2 (Menasche et al, 2003).…”

Section: Glp-1 Effects On the Readily Releasable Pool (Rrp)mentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

560

462

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…For conventional electron microscopy, mouse eyes were embedded as described previously, except eyes were postfixed in 1% osmium tetroxide alone (Futter et al, 2004). After embedding in Epon, 70-to 80-nm sections were cut and stained with lead citrate.…”

Section: Electron Microscopymentioning

confidence: 99%

“…After embedding in Epon, 70-to 80-nm sections were cut and stained with lead citrate. For cryo-immunoelectron microscopy (immunoEM), mouse eyes were fixed in 4% paraformaldehyde, 0.1% glutaraldehyde (for anx A2 staining) or 4% paraformaldehyde (for 1D4 staining) and then dissected, embedded in gelatin, infiltrated in sucrose, mounted on pins, and frozen in liquid nitrogen as described previously (Futter et al, 2004). Thawed 60-to 70-nm cryosections were labeled with affinity-purified rabbit anti-anx A2 polyclonal antibody (kindly provided by Dr. J. Ayala-Sanmartin) followed by 10-nm protein A gold, or 1D4 anti-rhodopsin mAb (Abcam, Cambridge, United Kingdom) followed by a rabbit anti-mouse bridging antibody and 15-nm protein A gold as described previously (Slot et al, 1991).…”

Section: Electron Microscopymentioning

confidence: 99%

Annexin A2 Regulates Phagocytosis of Photoreceptor Outer Segments in the Mouse Retina

Law

Hajjar

et al. 2009

MBoC

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The daily phagocytosis of shed photoreceptor outer segments by pigment epithelial cells is critical for the maintenance of the retina. In a subtractive polymerase chain reaction analysis, we found that functional differentiation of human ARPE19 retinal pigment epithelial (RPE) cells is accompanied by up-regulation of annexin (anx) A2, a major Src substrate and regulator of membrane-cytoskeleton dynamics. Here, we show that anx A2 is recruited to the nascent phagocytic cup in vitro and in vivo and that it fully dissociates once the phagosome is internalized. In ARPE19 cells depleted of anx A2 by using small interfering RNA and in ANX A2 ؊/؊ mice the phagocytosis of outer segments was impaired, and in ANX A2 ؊/؊ mice there was an accumulation of phagocytosed outer segments in the RPE apical processes, indicative of retarded phagosome transport. We show that anx A2 is tyrosine phosphorylated at the onset of phagocytosis and that the synchronized activation of focal adhesion kinase and c-Src is abnormal in ANX A2 ؊/؊ mice. These findings reveal that anx A2 is involved in the circadian regulation of outer segment phagocytosis, and they provide new insight into the protein machinery that regulates phagocytic function in RPE cells. INTRODUCTIONThe retinal pigment epithelium (RPE) performs a range of functions that directly support the retina (Strauss, 2005), including the daily phagocytosis and digestion of shed photoreceptor outer segments (POS). The importance of this activity is exemplified in the dystrophic Royal College of Surgeons rat, which due to a failure in phagocytosis undergoes a progressive and rapid retinal degeneration characterized by accumulation of cellular debris and photoreceptor cell death. The gene responsible for this pathology was identified by positional cloning as the Mer tyrosine kinase (MerTK), a key signaling intermediate that is expressed in RPE cells and plays an essential role in the internalization of bound POS (Chaitin and Hall, 1983;D'Cruz et al., 2000). Recent studies have provided insight into other RPE cell proteins that have distinct roles either in the binding or the internalization of shed POS. For example, the apically expressed ␣v␤5 integrin is required for efficient binding of POS, and RPE cells from ␤5 Ϫ/Ϫ mice show markedly reduced binding of POS in vitro (Nandrot et al., 2004). Intriguingly, engagement of the ␣v␤5 integrin by its cognate ligand, milk fat globule-EGF8 (MFG-E8), is essential for the circadian synchronization of phagocytosis (Nandrot and Finnemann, 2006;Nandrot et al., 2007), and although phagocytosis of POS occurs in MFG-E8 Ϫ/Ϫ and ␤5 Ϫ/Ϫ mice, in both mutants the daily rhythm is absent. In contrast, focal adhesion kinase (FAK) and MerTK are not required for the initial binding of POS to the apical surface of the RPE, but they are sequentially activated by ␣v␤5 receptors and are essential for phagosome internalization (Feng et al., 2002;Finnemann, 2003).Between the pigment epithelium and neuroretina RPE cells extend apical processes into the interphotorecept...

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The Role of Rab27a in the Regulation of Melanosome Distribution within Retinal Pigment Epithelial Cells

Cited by 95 publications

References 37 publications

Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Annexin A2 Regulates Phagocytosis of Photoreceptor Outer Segments in the Mouse Retina

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