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ABSTRACT: Transforming growth factor beta (TGF-beta) is an extracellular signaling molecule known to mediate programmed cell death (PCD) in the developing retina. In the present study, we investigated the expression profiles and activity levels of TGF-beta ligand and TGF-beta receptors (TbetaR) during the successive physiological PCD periods of the developing postnatal mouse retina. The peak of TbetaR expression levels--revealed by Western Blots and MLEC assays--coincided with the main periods of postnatal (P) retinal murine PCD at P2, P9, and P15. Immunocytochemical studies showed that the localization of the TbetaRs is restricted to the ganglion cell layer. Application of a neutralizing anti-TGF-beta antibody to E15 and P9 retinal cultures resulted in a significant decrease in the number of TUNEL-positive neurons specifically in the ganglion cell or prospective ganglion cell layer. Treatment of P2 and P15 organotypic murine retinal wholemount cultures with exogenous recombinant TGF-beta significantly increased cell death levels. In the P15 retina, where PCD affects ganglion cells and photoreceptors, TGF-beta induced cell death of large retinal ganglion cells, whereas small ganglion cells and photoreceptor neurons remained unaffected. Our data indicate that TGF-beta mediated apoptosis during all postnatal retinal PCD phases specifically affects the fate of retinal ganglion cells.
Neuroscience Research 11/2006; 56(2):193-203. · 2.25 Impact Factor
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ABSTRACT: 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.
The Journal of Comparative Neurology 04/2006; 495(3):263-78. · 3.81 Impact Factor
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ABSTRACT: Previous investigations revealed that fish inner ear otolith growth depends on the amplitude and the direction of gravity. Both otolith total size, otolith bilateral size-asymmetry and the total and bilateral calcium-incorporation are also affected by gravity. Hypergravity, e.g., slows down otolith growth and diminishes bilateral otolith asymmetry as compared to 1 g control specimens raised in parallel. Since the enzyme carbonic anhydrase (CA) plays a prominent role in otolithic calcification, the reactivity of inner ear CA during otolith growth under hypergravity was investigated. CA-reactivity was demonstrated histochemically and densitometrically on sections of inner ear maculae of larval cichlid fish (Oreochromis mossambicus), that were kept for 6 hrs in a 3 g hypergravity centrifuge. The total unilateral macular CA-reactivity and the bilateral difference in CA between the left and the right maculae were significantly lower in 3 g animals than in 1g controls. The result is in complete agreement with previous studies indicating that a regulatory mechanism, which adjusts otolith size and asymmetry towards the gravity vector, acts via activation/deactivation of macular CA.
Journal of Experimental Zoology Part A Comparative Experimental Biology 11/2004; 301(10):815-9.
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ABSTRACT: Larval cichlid fish (Oreochromis mossambicus) were kept at hypergravity (hg; centrifuge) for 6 h. Following the transfer to 1 g (i.e. stopping the centrifuge), animals were separated into normally and abnormally (kinetotic) swimming individuals (the latter were swimming kinetotically, i.e. performing spinning movements). Subsequently, carbonic anhydrase- (CA-) reactivity was histochemically demonstrated and densitometrically determined in inner ear maculae. It was found that both the total macular CA-reactivity as well as the difference in reactivates between left and right maculae were significantly lower in normally swimming hg-animals as compared to the kinetotically behaving hg-fish (P<0.0001). This result is in complete agreement with closely related studies carried out on the calcium incorporation of inner ear otoliths and indicates that a regulatory mechanism, which adjusts otolithic calcium carbonate incorporation towards the gravity vector, acts via activation/deactivation of macular CA.
Neuroscience Letters 01/2003; 335(1):17-20. · 2.11 Impact Factor
