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N. Duenker, A. Franke; Bi–phasic peak of expression levels of Transforming growth factor beta ligands and receptors coincide with the two main periods of retinal programmed cell death . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5325.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Programmed cell death (PCD) is a key phenomenon in the establishment of a cellular balance between cell proliferation and cell death. Although, many factors are known, mediating apoptosis, nothing is known about the molecular mechanisms regulating their expression and the cellular events defining why and which cell is going to die and when. As apoptosis is mediated by extracellular signalling via binding to specific cell surface receptors, one might speculate that (i) changes in expression or activity levels of death–related extracellular signalling molecules, peaking at PCD phases, or (ii) the combined expression of certain set of "death"–receptors on a certain cell determine, if a cell is destined to live or die. We have shown that reduction of endogenous transforming growth factor beta (TGF–beta) prevents apoptotic PCD of neurons in the developing peripheral and central nervous system (CNS). Recently we confirmed the pro–apoptotic role of endogenous TGF–beta in the developing chick and mouse retina. Methods: In order to further elucidate the underlying mechanism of TGF–beta mediated PCD in the chick retina, we investigated developmental changes in TGF–beta ligand and receptor expression pattern and activity level by Western Blot analyses of chick retinal extracts from embryonic day (E)3 to E16, in vitro activity assays (MLEC assay) and immunocytochemistry of retinal cross sections. Results: Western Blot analyses revealed that maximum expression levels of all TGF–beta receptors coincide with the two peaks of chick retinal PCD. Preliminary results indicate that the Bone morphogenetic protein receptors (BMPR) I and II also exhibits a regulated expression, paralleling the cell death phases. The activity of TGF–beta 2 and 3 ligands likewise peaks during the two main periods of cell death in the chick retina. In immunocytochemical stainings TGF–beta ligand and receptor expression was observed in cells in the ganglion cell layer and the inner nuclear layer, regions, PCD is confined to. Conclusions: Thus, TGF–beta might exert its pro–apoptotic effects at least partially via elevated activity and expression levels of TGF–beta ligands and receptors, which might be co–expressed with other "death" receptors, like BMPR, at that time. New insights in signalling pathways of apoptosis related extracellular signalling molecules and their receptors are highly clinically relevant with regard to multiple diseases with pathologically altered apoptis levels like neurodegenerative diseases, carcinogenesis and tumerogenesis.
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