Expression of Transforming Growth Factor-β Receptors in Normal Rat Retina and Experimental Choroidal Neovascularization

Yamanaka, Rie; Ogata, Nahoko; Yamamoto, Chihiro; Matsushita, Makoto; Matsuzaki, K; Uyama, M; Matsumura, Miyo

doi:10.1016/s0021-5155(02)00536-1

Cited by 10 publications

(5 citation statements)

References 33 publications

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“…Previous reports indicate the presence of multiple components of the TGF-β pathway in the developing retina, the adult retina and in cultured RGC (Yamanaka et al, 2002, Close et al, 2005, Ma et al, 2007). TGF-β signaling is complex, with autocrine and paracrine signaling reported for multiple cell types and widespread detection of both receptor and ligand expression (Gordon-Thomson et al, 1998, Guérin et al, 2001, Close et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

TGF-β signaling is required for maintenance of retinal ganglion cell differentiation and survival

2011

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Purpose To determine the role of TGF-β1 in the maintenance of retinal ganglion cell line (RGC-5) differentiation and integrity. Methods RGC-5 cells were differentiated in media conditioned by human non-pigmented ciliary epithelial cells (HNPE) for four days before treatment with TGF-β1 for 24 hr. Cells were examined for morphological changes and harvested for western blot and real-time PCR analysis. For study of apoptosis, differentiated RGC-5 cells were grown in serum-free medium for 24 hr in the presence or absence of TGF-β1 and collected for Annexin V/Propidium iodide FACs analysis. The role of MAPK pathways in TGF-β1-dependent signaling was determined by treatment with specific inhibitors of ERK, JNK and p38. Results Differentiation of RGC-5 cells in HNPE-conditioned media (CM) increased the neural cell markers, Brn-3c, NF-160, Thy1.2, Tau and PGP9.5. Treatment with TGF-β1 significantly increased the length of neurites extended by differentiated RGC-5s, concomitant with increased expression of NF-160 and PGP9.5, but not Brn-3c, Thy1.2 or Tau. TGF-β1 also decreased RGC-5 cell apoptosis in serum-free medium. p38 phosphorylation, but not smad2/3, JNK or ERK phosphorylation, was increased in TGF-β1 treated cells. Specific inhibition of p38 signaling reversed TGF-β1 induced neurite growth. Conclusions These findings demonstrate the induction of RGC-5 cell differentiation by HNPE derived CM and illustrate a role for TGF-β1 in maintaining RGC-5 cell survival and promoting neurite outgrowth through p38 MAPK.

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Section: Discussionmentioning

confidence: 99%

TGF-β signaling is required for maintenance of retinal ganglion cell differentiation and survival

2011

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“…TGF-β3 is not associated with microvascular cells, but is present in neural cells of the ganglion cell layer, the inner nuclear layer and some photoreceptor cells. The expression of TGF-receptors and pp-smad2 in normal retinas suggests that TGF-β plays an important role in the homeostasis of normal retina [52], with effects independent of the vasculature. These findings of impaired retinal function with inhibition of TGF-β have important implications for understanding both vasoproliferative and vascular degenerative retinal diseases.…”

Section: Discussionmentioning

confidence: 99%

TGF-β Is Required for Vascular Barrier Function, Endothelial Survival and Homeostasis of the Adult Microvasculature

et al. 2009

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Pericyte-endothelial cell (EC) interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-β signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-β signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-β signaling was inhibited by systemic expression of soluble endoglin (sEng) and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-β signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG). Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-β signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-β signaling. These results implicate constitutive TGF-β signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-β signaling in vasoproliferative and vascular degenerative retinal diseases.

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“…Insofar as apoptosis is mediated by extracellular signaling via binding to specific cell surface receptors, one might speculate that combined expression of a certain set of “death” receptors on a certain cell determines whether a cell is destined to live or die. Most studies published so far have dealt with the expression of TGF‐β isoforms and TβRs in human, monkey, or rat eyes (Pfeffer et al,1994; Obata et al,1995; Anderson et al,1995; Yamada et al,1999; Yamanaka et al,2002). Belecky‐Adams and Adler (2001) investigated the developmental expression of BMPs and receptors in specific stages of the chick retina (E3, E6, E8, E18) and found BMPRs to be expressed primarily in the ventral retina and in the optic stalk.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor‐β and bone morphogenetic proteins: Cooperative players in chick and murine programmed retinal cell death

Franke

Gubbe

Beier

et al. 2006

J of Comparative Neurology

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Transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) are extracellular molecules known to mediate programmed cell death (PCD) in the developing retina. In the present study, we investigated the expression profiles and activity levels of ligands and receptors of the TGF-beta and BMP4 family during the physiological PCD periods of the developing chick and mouse retina and possible interactions of both proapoptotic molecules in mediating apoptosis in chick and murine retinal whole-mount cultures. Immunocytochemical double-labeling studies with the established ganglion cell marker Islet revealed overlapping expression patterns for TGF-beta and BMP4 ligands and receptors on the surface of retinal ganglion cells. The biphasic peak of activity and expression levels of TGF-beta and BMP4 ligands and receptors, revealed by Western blots and mink lung epithelial cell (MLEC) assays, coincided with the two main periods of retinal chick and murine PCD. In organotypic retinal cultures, we were able to increase apoptosis over basal levels by application of recombinant TGF-beta or BMP4. Double-factor treatment induced an additional increase of apoptosis, suggesting a cooperation of both proapoptotic pathways. A significant increase in the number of apoptotic cells in the ganglion cell layer was observed in a TUNEL staining of retinal whole mounts treated with recombinant TGF-beta or BMP4, suggesting a concerted action of both factors in triggering ganglion cell death. Blockage experiments revealed that both pathways do not interact at the ligand, receptor, or Smad protein level but converge at the transcriptional level of the TGF-beta immediate-early response gene TIEG and the transcriptional coactivator Gcn5.

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Expression of Transforming Growth Factor-β Receptors in Normal Rat Retina and Experimental Choroidal Neovascularization

Cited by 10 publications

References 33 publications

TGF-β signaling is required for maintenance of retinal ganglion cell differentiation and survival

TGF-β signaling is required for maintenance of retinal ganglion cell differentiation and survival

TGF-β Is Required for Vascular Barrier Function, Endothelial Survival and Homeostasis of the Adult Microvasculature

Transforming growth factor‐β and bone morphogenetic proteins: Cooperative players in chick and murine programmed retinal cell death

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