Daniel E. Syroid,1 Todd S. Zorick,1,3 Christophe Arbet-Engels,2 Trevor J. Kilpatrick,1 Walter Eckhart,2 and Greg Lemke1
1Molecular Neurobiology Laboratory and 2Molecular Biology and Virology Laboratory, The Salk Institute for BiologicalStudies, La Jolla, California 92037, and 3Department of Neurosciences, University of California San Diego, La Jolla, California 92093

During postnatal development in the peripheral nerve, differentiating Schwann cells are susceptible to apoptotic death. Schwann cell apoptosis is regulated by axons and serves as one mechanism through which axon and  Schwann cell numbers are correctly matched. This regulation is mediated in part by the provision of limiting axon-derived trophic molecules, although neuregulin-1 (NRG-1) is the only trophic factor shownto date to support  Schwann cell survival. In this report, we identify insulin-like growth factor-I (IGF-I) as an additional trophin that can promote Schwann cell survival in vitro. We find that IGF-I, like NRG-1, can prevent the apoptotic death of postnatal rat Schwann cells cultured under conditions of serum withdrawal. Moreover, we show that differentiating Schwann cells in the rat sciatic nerve express both the IGF-I receptor (IGF-I R) and IGF-I throughout  postnatal development. These results indicate that IGF-I is likely to control Schwann cell viability in the developing peripheral nerve and, together with other findings, raise the interesting possibility that such survival regulation may switch during postnatal development from an axon-dependent mechanism to an autocrine and/or paracrine one.
Key words: peripheral nervous system; glia; Schwann cell; myelination; apoptosis; insulin-like growth factor-I

Programmed death is a cell fate adopted by multicellular organisms to control cell number in development, homeostasis, and defense. Such physiological cell death, which most often proceeds through a series of well-defined  alterations in cellular morphology termed apoptosis, is genetically programmed and results in cell suicide. Importantly, apoptosis must be tightly regulated such that only certain cells are specified to die, and it is now clear that both cell-extrinsic and cell-intrinsic signals can render cells susceptible to apoptosis (Steller, 1995; Fraser et al., 1996; White, 1996). During development, programmed cell death is often controlled by the positive  selection of cells via specific ligand–receptor tyrosine kinase interactions. Approximately 50% of immature postmitotic neurons normally undergo apoptotic death. In this instance, extrinsic signals delimit neuronal number and establish appropriate innervation patterns through competition for limiting target-derived trophins (Barde, 1989; Oppenheim, 1991). Death occurs when neurons fail to secure access to these trophins and consequently are unable to suppress a constitutive cell death program (Raff, 1992; Raff et al., 1993). Apoptosis also occurs in differentiating oligodendrocytes and Schwann cells, the myelinating glial cells of the CNS and peripheral nervous  system, respectively. Approximately 50% of newly generated oligodendrocytes die during development of the rodent optic nerve (Raff et al., 1993; Barres and Raff, 1994), and differentiating Schwann cells undergo apoptotic death during both embryonic (Ciutat et al., 1996) and early postnatal (Grinspan et al., 1996; Syroid et al., 1996; Nakao et al., 1997) development.  Cell death in these glial lineages is thought to be in part regulated by the limited availability of axon-derived trophic factors and represents one mechanism whereby the appropriate stoichiometry between glia and the axons they myelinate is achieved (Raff et al., 1993; Barres and Raff, 1994; Zorick and emke, 1996). Understanding the regulation of Schwann cell apoptosis requires an identification of the trophins that control Schwann cell viability. Apoptosis in Schwann cell precursors in vitro (Dong et al., 1995) and in  postnatal Schwann cells in vivo (Grinspan et al., 1996; Trachtenberg and Thompson, 1996; Kopp et al., 1997) and in vitro (Syroid et al., 1996) can be prevented by neuregulin-1 (NRG-1), which is normally supplied by axons  (Carraway and Burden, 1995; Lemke, 1996). Another set of factors that may mediate Schwann cell survival is the insulin-like growth factors (IGFs)-I and -II. As autocrine and/or paracrine factors, the IGFs are thought to play  an important role in the development an regeneration of the nervous system (Hansson, 1993; Ishii et al., 1993; Lewis et al., 1993a; de Pablo and de la Rosa, 1995). IGF-I, for example, regulates oligodendrocyte development  and myelination in vitro and in vivo (McMorris et al., 1986, 1993; McMorris and Dubois-Dalcq, 1988; Saneto et al., 1988; Mozell and McMorris, 1991; Barres and Raff, 1994; Yao et al., 1995). Reduced Received Oct. 23, 1998; revised Dec. 22, 1998; accepted Dec. 28, 1998. This work was supported by postdoctoral fellowships from the National Multiple Sclerosis Society to D.E.S. and from the Howard Hughes Medical Institute and the Bushell  Fellowship of the Royal Australasian College of Physicians to T.J.K., by predoctoral fellowships from the Department of Defense and the National Institutes of Health to T.S.Z., and by grants from the National Institutes of   Health to W.E. and G.L. We thank Danny Ortun˜o, Patrick Burrola, and Darcie Baynes for excellent technical assistance, Stefano Bertuzzi for help with RNase protection assays, Dan Peterson of the Gage laboratory for use of  their confocal microscope, Jill Meisenhelder  or peptide synthesis, and Bob Hyman for kindly providing anti-Thy-1antibodies.

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