TGF-beta modulates programmed cell death in the retina of the developing chick embryo.
Programmed cell death (PCD) is a key phenomenon in the regulation of cell number in multicellular organisms. 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, suggesting that TGF-beta is an important mediator of ontogenetic neuron death. Previous studies suggested that there are other pro-apoptotic molecules, nerve growth factor (NGF) and brain-derived neurotrophic factor, that induce cell death in the nervous system. In the developing chick retina, NGF induces PCD by activation of the p75 receptor. We have studied the role of TGF-beta and its putative interdependence with NGF-mediated PCD in the chick retina. We found that TGF-beta is present in the developing chick retina during the period of PCD and is essentially required to regulate PCD of retinal cells. TGF-beta 2, TGF-beta 3 and the ligand-binding TGF-beta receptor can be detected immunocytochemically in the central retina, a region where apoptosis is most prominent during the early period of PCD. Application of a TGF-beta-neutralizing antibody to chick embryos in ovo resulted in a decrease in the number of TUNEL-positive cells and a reduction of free nucleosome levels. In terms of magnitude, reduction of PCD caused by the neutralization of endogenous TGF-beta was equivalent to that seen after anti-NGF application. Neutralization of both factors did not result in a further decrease in apoptosis, indicating that NGF and TGF-beta may act on the same cell population. Furthermore, neutralization of TGF-beta did not affect the expression of NGF or the p75-receptor. Our results suggest that TGF-beta and NGF are both required to regulate cell death in the chick retina in vivo.
Dünker
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University of Saarland, Department of Anatomy, D-66421 Homburg/Saar, Germany.
Schuster
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N
Krieglstein
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K
D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002455:Cell Division; D002642:Chick Embryo; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000196:embryology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D009414:Nerve Growth Factors; D020033:Protein Isoforms; D020800:Receptor, Nerve Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D010749:Phosphoprotein Phosphatases