Transforming Growth Factor‐β (TGF‐β) and Programmed Cell Death in the Vertebrate Retina
Introduction
TGF‐βs are multifunctional cytokines with a broad distribution pattern (Flanders 1991, Jakowlew 1994, Unsicker 1991). TGF‐βs appear in three highly homologous isoforms, TGF‐β1, ‐β2, and ‐β3, encoded by three different, but closely related genes. TGF‐β1 is the prototype of a growing superfamily of peptide‐growth factors, containing the TGF‐β family, activin/inhibin family, bone morphogenetic protein (BMP) family, Müllerian inhibiting substance, glial cell‐derived neurotrophic factor (GDNF), and certain other factors (Miyazono 1994a, Miyazono 1994b). All superfamily members are characterized by structural similarities and similar signaling cascades but reveal functional diversities (Itoh 2000, Massague 1990, Massague 2000, Roberts 1990). TGF proteins are disulfide‐bound homodimers with a molecular weight of 25 kDa, synthesized as propeptides of different length. These precursor proteins are cleaved, releasing a C‐terminal, disulfide‐bound protein. The amino acid sequence of the released, active C‐terminal protein is highly conserved among the TGF‐β isoforms. The expression of TGF‐β starts early in the development of the nervous system. Each TGF‐β isoform exhibits a distinct spatial and temporal expression pattern and the distribution of two isoforms often overlaps (Flanders 1991, Flanders 1993, Gatherer 1990, Millan 1991, Pelton 1990, Pelton 1991, Schmid 1991, Unsicker 1996).
During development, TGF‐βs are expressed in different tissues like bone, cartilage, teeth, skin, gut, liver, kidney, heart, blood vessels, eye, and nervous system (Pelton et al., 1991). A strong expression profile has been found in areas undergoing morphological changes, especially those with profound epithelia–mesenchymal interactions (Krieglstein 1995, Krieglstein 1998a, Lehnert 1988).
TGF‐βs were first described as factors capable of inducing adhesion‐independent growth of kidney cells from rat and in a fibroblast cell line (Moses 1981, Roberts 1981). However, the biological activity of TGF‐βs is not restricted to these effects. In fact, TGF‐βs are multifunctional factors with a wide spectrum of activities including cell cycle control, regulation of early developmental and differentiating processes, formation of extracellular matrix, hematopoiesis, angiogenesis, chemotaxis, and immune functions (Boettner 2000, Duenker 2000, Lawrence 1996, Mummery 2001, Saltis 1996, Schuster 2002).
TGF‐βs are contextually acting molecules (Nathan 1991, Schuster 2000, Unsicker 2000), meaning that depending on the cell type, the differentiation status, the cellular environment, and the presence or absence of certain other factors TGF‐βs either stimulate or repress cell proliferation (Ashley 1998, Combs 2000, Gold 1999, Roberts 1990), act neurotrophic (Krieglstein 1998a, Krieglstein 1998b), or induce cell death (de Luca 1996, Hata 1998, Krieglstein 2000).
The majority of studies published so far dealt with the expression of TGF‐β isoforms and TβRs in human, monkey, or rat eyes (Ikeda 1998, Lutty 1991, Lutty 1993, Pfeffer 1994, Yamada 1999). Immunohistochemical evidence of TGF‐β expression in the retina was first obtained from human eyes where immunoreactivity was reported to be associated with photoreceptor outer segments (Anderson 1995, Lutty 1991, Lutty 1993, Pfeffer 1994). Pena et al. (1999) demonstrated the presence of TGF‐β2 in fetal and glaucomatous adult human optic nerve heads. TGF‐β2 was found to be the predominant endogenous isoform in the vitreous humor and retinal pigment epithelium (RPE) of monkey eyes (Pfeffer et al., 1994). Obata 1995, Obata 1999, Yamanaka 2002 reported on the expression of TβRs in the cornea, ciliary body, iris, lens retinal cells, and pigment epithelium of rat eyes.
We were the first to report on the distribution pattern of TGF‐β2 and ‐3 isoforms and TβRI and II in the developing chick and mouse retina (Duenker 2003, Duenker 2001). In the developing chick retina (Duenker et al., 2001) as well as in the embryonic mouse eye (Duenker and Krieglstein, 2003) expression of TGF‐β isoforms is associated with the optic nerve region, an area where apoptosis is most prominent during the period of programmed cell death (Frade and Barde, 1999).
When we examined the presence of TβRI, TβRII, TGF‐β2, and TGF‐β3 immunoreactivities in the embryonic [embryonic day (E) 13.5–E15.5] wild‐type mouse retina (Duenker and Krieglstein, 2003), we found signals for TβRI and TβRII in the inner retina, in the future optic fiber layer, as well as in the cornea and in the lens epithelium or lens fibers. Both TGF‐β isoforms were expressed in the central retina and the signal was more prominent in the region of the optic nerve head and to the prospective optic fiber layer.
Section snippets
Functions of Programmed Cell Death
Programmed cell death (PCD) is a key phenomenon in regulating cell numbers in multicellular organisms. PCD tunes the establishment of a balance between cell proliferation and apoptosis during development but also crucially regulates the maintenance of an adult tissue homeostasis. In many organs including the developing nervous system neurons and glial cells are produced extensively and the final number of cells is adjusted by PCD (Barde 1989, Henderson 1996, Jacobson 1997, Oppenheim 1991).
TGF‐β‐Mediated Programmed Retinal Cell Death In Vitro
We have recently shown that TGF‐β plays an important role in mediating ontogenetic PCD in the nervous system since in ovo neutralization of endogenous TGF‐β during early chick embryogenesis abolishes apoptosis of specific neuronal populations (Krieglstein et al., 2000).
We were the first group to investigate the role of TGF‐βs in mediating PCD in the retina in vitro. We used a retinal cell culture system of dissociated primary retinal neurons from 7‐day‐old chick embryos (Schuster et al., 2002b
Interaction of TGF‐β with Other Pro‐ and Antiapoptotic Factors in Mediating Retinal Apoptosis
Many of the typical actions of TGF‐βs are context dependent. Its actions often depend on environmental cues (i.e., the cell type or the differentiated state of cells best exemplified by its capacity to either stimulate or inhibit proliferation) (Ashley 1998, Nathan 1991, Roberts 1990, Skoff 1998). It has been shown that TGF‐βs are subject to the coregulatory activities of other growth factors (Ashley 1998, Duenker 2001, Massague 2000, Roberts 1990). Most recently, ten Dijke and Hill (2004)
Conclusions and Perspectives
In conclusion, all data gained so far indicate a pivotal role of TGF‐β in mediating PCD in the vertebrate retina (Table I). We were the first to show that endogenous TGF‐β is required for cell death occurring in the developing chick retina in vivo, which was previously attributed only to NGF (Duenker et al., 2001). The analysis of the developing retina of Tgfβ2−/−Tgfβ3−/− mutant mice and their three allelic Tgfβ2−/−Tgfβ3+/− and Tgfβ2+/−Tgfβ3−/− littermates verified the role of TGF‐βs in
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Work done in part at previous address: Center for Anatomy, Department of Neuroanatomy, University of Göttingen; 37075 Göttingen, Germany