In Vivo Analysis of Schwann Cell Programmed Cell Death in the Embryonic Chick: Regulation by Axons and Glial Growth Factor

Abstract

The present study uses the embryonic chick to examine in vivo the mechanisms and regulation of Schwann cell programmed cell death (PCD) in spinal and cranial peripheral nerves. Schwann cells are highly dependent on the presence of axons for survival because the in ovo administration of NMDA, which excitotoxically eliminates motoneurons and their axons by necrosis, results in a significant increase in apoptotic Schwann cell death. Additionally, pharmacological and surgical manipulation of axon numbers also affects the relative amounts of Schwann cell PCD. Schwann cells undergoing both normal and induced PCD display an apoptotic-like cell death, using a caspase-dependent pathway. Furthermore, axon elimination results in upregulation of the p75 and platelet-derived growth factor receptors in mature Schwann cells within the degenerating ventral root. During early development, Schwann cells are also dependent on axon-derived mitogens; the loss of axons results in a decrease in Schwann cell proliferation. Axon removal during late embryonic stages, however, elicits an increase in proliferation, as is expected from these more differentiated Schwann cells. In rodents, Schwann cell survival is regulated by glial growth factor (GGF), a member of the neuregulin family of growth factors. GGF administration to chick embryos selectively rescued Schwann cells during both normal PCD and after the loss of axons, whereas other trophic factors tested had no effect on Schwann cell survival. In conclusion, avian Schwann cells exhibit many similarities to mammalian Schwann cells in terms of their dependence on axon-derived signals during early and later stages of development.

Neurotrophins Induce Neuregulin Release through Protein Kinase Cδ Activation

“…We postulate that PKC␦ activation leads to the phosphorylation of specific serine residues on the pro-NRG1 cytoplasmic tail, which rapidly promotes its cleavage and subsequent release of soluble NRG1 from the axon at sites near where it is activated. Once released, NRG1 can then bind and activate its receptors on the adjacent cell, which, in the case of developing Schwann cells, is critical for their survival and differentiation (67). PKC activation has been shown to be essential for the regulated release of many other transmembrane signaling proteins that release their active ectodomains raising the possibility that similar, localized signaling mechanism could result in their processing and release as well (42, 68 -70).…”

Development of the Schwann cell lineage: From the neural crest to the myelinated nerve

“…In both cases, the signal was identified as NRG1 (Dong et al, 1995(Dong et al, , 1999Jessen et al, 1994). Similarly, pharmacological and surgical-induced death of axons contributes to apoptotic Schwann cell death, and exogenous NRG1 administration can rescue death, induced by loss of axons (Ciutat et al, 1996;Winseck et al, 2002). Embryonic DRG axons and motor neurons express NRG1, which accumulates along axonal tracts (Falls et al, 1993;Loeb et al, 1999;Marchionni et al, 1993;Orr-Urtreger et al, 1993, Taveggia et al, 2005 and would therefore be available at the right time to regulate precursor survival.…”

Rapid Axoglial Signaling Mediated by Neuregulin and Neurotrophic Factors

“…During nerve development, Schwann cells migrate along axons and intensively proliferate, producing more Schwann cells than are actually needed. Subsequently, these "excess" Schwann cells are eliminated by programmed cell death in a manner similar to excess neurons being eliminated during development (Oppenheim, 1996;Caldero et al, 1998;Winseck et al, 2002). The search for axonal factors responsible for the proliferation of Schwann cells has led to the identification of a soluble, heparin-binding axonal activity initially named glial growth factor that was later found to belong to a group of alternatively spliced factors produced by the NRG1 gene (Marchionni et al, 1993;Lemke, 1996).…”

“…Disruption of NRG signaling between axons and Schwann cells, by directly knocking out either the entire NRG-1 gene or the genes encoding its receptors, erbB2 and erbB3, leads to an almost complete loss of Schwann cells, followed thereafter by death of the sensory and motor neurons that they support (Meyer and Birchmeier, 1995;Riethmacher et al, 1997;Morris et al, 1999;Woldeyesus et al, 1999;Adlkofer and Lai, 2000;Garratt et al, 2000). These effects are likely attributable to the effects of NRG on Schwann cell proliferation and early survival (Ciutat et al, 1996;Grinspan et al, 1996;Trachtenberg and Thompson, 1996;Winseck et al, 2002). Later, selective blockade of erbB signaling in nonmyelinating Schwann cells produces a progressive sensory neuropathy with subsequent loss of DRG neurons (Chen et al, 2003).…”

“…Soluble forms of NRG may also be important for peripheral nerve development, because NRG blocks normal and NMDA and denervation-induced Schwann cell programmed cell death (Kopp et al, 1997;Winseck et al, 2002). Because Schwann cells express neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4, and glial cell line-derived neurotrophic factor (GDNF) (Funakoshi et al, 1993;Henderson et al, 1994;Griesbeck et al, 1995;Friedman et al, 1996), they could similarly promote the release of NRG from axons.…”