Tyrosinase biosynthesis in adult mammalian retinal pigment epithelial cells

Schraermeyer, Ulrich; Kopitz, Jürgen; Peters, Swaantje; Henke-Fahle, Sigrid; Blitgen-Heinecke, Petra; Kokkinou, D.; Schwarz, Tobias; Bartz-Schmidt, Karl-Ulrich

doi:10.1016/j.exer.2005.12.015

Cited by 43 publications

(33 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MITF is a master regulatory gene for survival of melanocytes (Tassabehji et al, 1994;Goding, 2000) and a key transcription factor that regulates the expression of TYR, the rate-limiting en-zyme responsible for melanin biosynthesis in the RPE (Schraermeyer et al, 2006;Wang and Hebert, 2006). To examine the effect of KL on melanogenesis, we cultured primary human RPE cells.…”

Section: Kl Regulates Melanogenesis and Pigment Synthesis In Rpementioning

confidence: 99%

Klotho Regulates Retinal Pigment Epithelial Functions and Protects Against Oxidative Stress

et al. 2013

View full text Add to dashboard Cite

The retinal pigment epithelium (RPE) is a highly specialized CNS tissue that plays crucial roles in retinal homeostasis. Age-related morphological changes in the RPE have been associated with retinal degenerative disorders; our understanding of the underlying molecular mechanisms, however, remains incomplete. Here we report on a key role of Klotho (Kl), an aging-suppressor gene, in retinal health and RPE physiology. Kl Ϫ / Ϫ mice show RPE and photoreceptor degeneration, reduced pigment synthesis in the RPE, and impaired phagocytosis of the outer segment of the photoreceptors. Klotho protein (KL) is expressed in primary cultured human RPE, and regulates pigment synthesis by increasing the expression of MITF (microphthalmia transcription factor) and TYR (tyrosinase), two pivotal genes in melanogenesis. Importantly, KL increases phagocytosis in cultured RPE by inducing gene expression of MERTK/AXL/TYRO3. These effects of KL are mediated through cAMP-PKA-dependent phosphorylation of transcription factor CREB. In cultured human RPE, KL increases the L-3,4-dihydroxyphenylalanine synthesis and inhibits vascular endothelial growth factor (VEGF) secretion from basal membrane by inhibiting IGF-1 signaling and VEGF receptor 2 phosphorylation. KL also regulates the expression of stress-related genes in RPE, lowers the production of reactive oxygen species, and thereby, protects RPE from oxidative stress. Together, our results demonstrate a critical function for KL in mouse retinal health in vivo, and a protective role toward human RPE cells in vitro. We conclude that KL is an important regulator of RPE homeostasis, and propose that an age-dependent decline of KL expression may contribute to RPE degeneration and retinal pathology.

show abstract

Section: Kl Regulates Melanogenesis and Pigment Synthesis In Rpementioning

confidence: 99%

Klotho Regulates Retinal Pigment Epithelial Functions and Protects Against Oxidative Stress

et al. 2013

View full text Add to dashboard Cite

show abstract

“…[63][64][65] In addition, phagocytosis of retinal outer segment promotes tyrosinase biosynthesis, and RPE cell pigmentation is an indication of the cell maturity and functionality. 66 In a recent report, Schwartz et al reported greater attachment and spreading of the hESC-RPE with lower degree of pigmentation compared with darkly pigmented cells after culture. This data suggests that the extent of hESC-RPE maturity and pigmentation in vitro might substantially affect the attachment of transplanted cells to BM and their subsequent survival and integration to the host RPE layer.…”

Section: Discussionmentioning

confidence: 99%

Structure and Barrier Properties of Human Embryonic Stem Cell–Derived Retinal Pigment Epithelial Cells Are Affected by Extracellular Matrix Protein Coating

Sorkio

Hongisto

Kaarniranta

et al. 2014

Tissue Engineering Part A

View full text Add to dashboard Cite

Extracellular matrix (ECM) interactions play a vital role in cell morphology, migration, proliferation, and differentiation of cells. We investigated the role of ECM proteins on the structure and function of human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells during their differentiation and maturation from hESCs into RPE cells in adherent differentiation cultures on several human ECM proteins found in native human Bruch's membrane, namely, collagen I, collagen IV, laminin, fibronectin, and vitronectin, as well as on commercial substrates of xeno-free CELLstartÔ and MatrigelÔ. Cell pigmentation, expression of RPE-specific proteins, fine structure, as well as the production of basal lamina by hESC-RPE on different protein coatings were evaluated after 140 days of differentiation. The integrity of hESC-RPE epithelium and barrier properties on different coatings were investigated by measuring transepithelial resistance. All coatings supported the differentiation of hESC-RPE cells as demonstrated by early onset of cell pigmentation and further maturation to RPE monolayers after enrichment. Mature RPE phenotype was verified by RPE-specific gene and protein expression, correct epithelial polarization, and phagocytic activity. Significant differences were found in the degree of RPE cell pigmentation and tightness of epithelial barrier between different coatings. Further, the thickness of self-assembled basal lamina and secretion of the key ECM proteins found in the basement membrane of the native RPE varied between hESC-RPE cultured on compared protein coatings. In conclusion, this study shows that the cell culture substrate has a major effect on the structure and basal lamina production during the differentiation and maturation of hESC-RPE potentially influencing the success of cell integrations and survival after cell transplantation.

show abstract

“…Several studies have reported an absence of tyrosinase and/or tyrosinase-related protein expression in adult RPE (Miyamoto and Fitzpatrick, 1957;Smith-Thomas et al, 1996). However, tyrosinase activity has been detected in extracts from adult RPE (Dryja et al, 1978;Varela et al, 1995), and tyrosinase expression/activity was detected in cultured adult RPE cells (Basu et al, 1983;Dorey et al, 1990), and it was increased after incubation with rod outer segments (Schraermeyer et al, 2006). Vacuoles with the morphological characteristics of immature melanosomes have been described in adult RPE (Schraermeyer, 1993;Schraermeyer and Heimann, 1999), but pmel17 staining in adult RPE has not been reported.…”

Section: The Timing Of Melanosome Formation In Ocular Tissuesmentioning

confidence: 99%

Melanosome Maturation Defect in Rab38-deficient Retinal Pigment Epithelium Results in Instability of Immature Melanosomes during Transient Melanogenesis

Lopes

Wasmeier

Seabra

et al. 2007

MBoC

View full text Add to dashboard Cite

Pathways of melanosome biogenesis in retinal pigment epithelial (RPE) cells have received less attention than those of skin melanocytes. Although the bulk of melanin synthesis in RPE cells occurs embryonically, it is not clear whether adult RPE cells continue to produce melanosomes. Here, we show that progression from pmel17-positive premelanosomes to tyrosinase-positive mature melanosomes in the RPE is largely complete before birth. Loss of functional Rab38 in the "chocolate" (cht) mouse causes dramatically reduced numbers of melanosomes in adult RPE, in contrast to the mild phenotype previously shown in skin melanocytes. Choroidal melanocytes in cht mice also have reduced melanosome numbers, but a continuing low level of melanosome biogenesis gradually overcomes the defect, unlike in the RPE. Partial compensation by Rab32 that occurs in skin melanocytes is less effective in the RPE, presumably because of the short time window for melanosome biogenesis. In cht RPE, premelanosomes form but delivery of tyrosinase is impaired. Premelanosomes that fail to deposit melanin are unstable in both cht and tyrosinase-deficient RPE. Together with the high levels of cathepsin D in immature melanosomes of the RPE, our results suggest that melanin deposition may protect the maturing melanosome from the activity of lumenal acid hydrolases.

show abstract

Tyrosinase biosynthesis in adult mammalian retinal pigment epithelial cells

Cited by 43 publications

References 38 publications

Klotho Regulates Retinal Pigment Epithelial Functions and Protects Against Oxidative Stress

Klotho Regulates Retinal Pigment Epithelial Functions and Protects Against Oxidative Stress

Structure and Barrier Properties of Human Embryonic Stem Cell–Derived Retinal Pigment Epithelial Cells Are Affected by Extracellular Matrix Protein Coating

Melanosome Maturation Defect in Rab38-deficient Retinal Pigment Epithelium Results in Instability of Immature Melanosomes during Transient Melanogenesis

Contact Info

Product

Resources

About