Transforming Growth Factor β (TGFβ) Mediates Schwann Cell DeathIn VitroandIn Vivo: Examination of c-Jun Activation, Interactions with Survival Signals, and the Relationship of TGFβ-Mediated Death to Schwann Cell Differentiation

Abstract

In some situations, cell death in the nervous system is controlled by an interplay between survival factors and negative survival signals that actively induce apoptosis. The present work indicates that the survival of Schwann cells is regulated by such a dual mechanism involving the negative survival signal transforming growth factor beta (TGFbeta), a family of growth factors that is present in the Schwann cells themselves. We analyze the interactions between this putative autocrine death signal and previously defined paracrine and autocrine survival signals and show that expression of a dominant negative c-Jun inhibits TGFbeta-induced apoptosis. This and other findings pinpoint activation of c-Jun as a key downstream event in TGFbeta-induced Schwann cell death. The ability of TGFbeta to kill Schwann cells, like normal Schwann cell death in vivo, is under a strong developmental regulation, and we show that the decreasing ability of TGFbeta to kill older cells is attributable to a decreasing ability of TGFbeta to phosphorylate c-Jun in more differentiated cells.

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

“…Consistent with the finding that TGF-β3 is the primary isoform increased in diabetic sciatic nerve, TGF-β3 produced the greatest reduction in neurite growth. These findings are consistent with previous observations that TGF-β blocks the myelination of axons (Guenard et al, 1995) and mediates the death of mature SCs resulting in axonal injury (Parkinson et al, 2001). …”

“…In the current study, increased glucose and TGF-β1 or TGF-β2 in combination produced greater neuronal injury in embryonic DRG than TGF-β used alone. There are several possible pathways by which TGF-β can induce cell and axonal injury including induction of ROS (Jardine et al, 2002;Yao et al, 2007); by activation of programmed cell death pathways including activation of caspases, Smads, release of cytochrome c; and by down regulating antiapoptotic Bcl proteins for example Bcl2 and Bcl-X L , while up regulating proapoptotic proteins (Bax and Bad) (Barna et al, 2002;Derynck and Zhang 2003;Parkinson et al, 2001;Schuster and Krieglstein 2002;Ten Dijke et al, 2002).…”

Analysis of congenital hypomyelinating Egr2 Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination

“…8B). Indeed, TGF␤1 has demonstrated to be important modulator of Schwann cell phenotype and an activator of Jun (27,28). A group of genes involved in lipid catabolism, including Abc1 and Cpt1a, was also identified in this subset.…”

Transforming Growth Factor Beta in the Central Nervous System

“…A role of TGF-β in the differentiation and survival of other, as yet unexplored neuronal cell types might also be possible. As far as glial cells, data are available that in the peripheral nervous system, TGF-β regulates the degree of Schwann cell proliferation induced by neuronal contact (Guenard et al, 1995;Parkinson et al, 2001). …”