Development, Vol 120, Issue 6 1399-1409, Copyright © 1994 by Company of Biologists

JOURNAL ARTICLES

Negative regulation of the P0 gene in Schwann cells: suppression of P0 mRNA and protein induction in cultured Schwann cells by FGF2 and TGF beta 1, TGF beta 2 and TGF beta 3

L Morgan, KR Jessen and R Mirsky
Department of Anatomy and Developmental Biology, University College London, UK.

During the development of peripheral nerves, Schwann cells are induced to form myelin sheaths round the larger axons. This process involves a complex series of events and the nature of the molecular signals that regulate and control myelin formation in Schwann cells is not well understood. Our previous experiments on rat Schwann cells in vitro, using serum-free defined medium, showed that a myelin-related protein phenotype could be induced in early postnatal Schwann cells in culture by elevation of intracellular cyclic AMP levels in the absence of growth factors, conditions under which the cells are not dividing. Cells with this phenotype expressed the major myelin glycoprotein P0 and expression of p75 NGF receptor, N-CAM, GFAP and A5E3 proteins was down-regulated. These changes are all characteristics associated with myelination in vivo. In contrast, when cyclic AMP levels were elevated in the presence of serum, suppression of cyclic AMP-induced differentiation resulted and DNA synthesis was induced. In this paper, we have used this model system and extended our analysis to explore the relationship between defined growth factors and suppression of myelination. We have used pure recombinant growth factors normally present in peripheral nerves, i.e. FGF1 and FGF2 and TGF beta 1, TGF beta 2, and TGF beta 3 and shown that, like serum, they can strongly suppress the forskolin-mediated induction of the P0 gene, both at the level of mRNA and protein synthesis. For both growth factor families, the suppression of P0 gene expression is dose-dependent and takes place in serum-starved cells that are mitotically quiescent. In the case of FGF2, however, even more complete suppression is obtained when the cells are simultaneously allowed to enter the cell cycle by inclusion of high concentrations of insulin in the culture medium. The present results raise the possibility that, in addition to the positive axonal signals that are usually envisaged to control the onset of myelination, growth factors present in the nerve may exert negative regulatory signals during development and thus help control the time of onset and the rate of myelination in peripheral nerves.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. Freidin, S. Asche, T. A. Bargiello, M. V. L. Bennett, and C. K. Abrams Connexin 32 increases the proliferative response of Schwann cells to neuregulin-1 (Nrg1) PNAS, March 3, 2009; 106(9): 3567 - 3572. [Abstract] [Full Text] [PDF]

				D. B. Parkinson, A. Bhaskaran, P. Arthur-Farraj, L. A. Noon, A. Woodhoo, A. C. Lloyd, M. L. Feltri, L. Wrabetz, A. Behrens, R. Mirsky, et al. c-Jun is a negative regulator of myelination J. Cell Biol., October 17, 2008; 181(4): 625 - 637. [Abstract] [Full Text] [PDF]

				M. D'Antonio, A. Droggiti, M. L. Feltri, J. Roes, L. Wrabetz, R. Mirsky, and K. R. Jessen TGFbeta Type II Receptor Signaling Controls Schwann Cell Death and Proliferation in Developing Nerves. J. Neurosci., August 15, 2006; 26(33): 8417 - 8427. [Abstract] [Full Text] [PDF]

				D. B. Parkinson, A. Bhaskaran, A. Droggiti, S. Dickinson, M. D'Antonio, R. Mirsky, and K. R. Jessen Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death J. Cell Biol., February 2, 2004; 164(3): 385 - 394. [Abstract] [Full Text] [PDF]

				S. G. Slutsky, A. K. Kamaraju, A. M. Levy, J. Chebath, and M. Revel Activation of Myelin Genes during Transdifferentiation from Melanoma to Glial Cell Phenotype J. Biol. Chem., March 7, 2003; 278(11): 8960 - 8968. [Abstract] [Full Text] [PDF]

				A. Tabernero, A. Velasco, B. Granda, E. M. Lavado, and J. M. Medina Transcytosis of Albumin in Astrocytes Activates the Sterol Regulatory Element-binding Protein-1, Which Promotes the Synthesis of the Neurotrophic Factor Oleic Acid J. Biol. Chem., February 1, 2002; 277(6): 4240 - 4246. [Abstract] [Full Text] [PDF]

				D. B. Parkinson, Z. Dong, H. Bunting, J. Whitfield, C. Meier, H. Marie, R. Mirsky, and K. R. Jessen Transforming Growth Factor beta (TGFbeta ) Mediates Schwann Cell Death In Vitro and In Vivo: Examination of c-Jun Activation, Interactions with Survival Signals, and the Relationship of TGFbeta -Mediated Death to Schwann Cell Differentiation J. Neurosci., November 1, 2001; 21(21): 8572 - 8585. [Abstract] [Full Text] [PDF]

				G. Zanazzi, S. Einheber, R. Westreich, M.-J. Hannocks, D. Bedell-Hogan, M. A. Marchionni, and J. L. Salzer Glial Growth Factor/Neuregulin Inhibits Schwann Cell Myelination and Induces Demyelination J. Cell Biol., March 19, 2001; 152(6): 1289 - 1300. [Abstract] [Full Text] [PDF]

				H. S. Keirstead, T. Ben-Hur, B. Rogister, M. T. O'Leary, M. Dubois-Dalcq, and W. F. Blakemore Polysialylated Neural Cell Adhesion Molecule-Positive CNS Precursors Generate Both Oligodendrocytes and Schwann Cells to Remyelinate the CNS after Transplantation J. Neurosci., September 1, 1999; 19(17): 7529 - 7536. [Abstract] [Full Text] [PDF]

				D. E. Weinstein Review : The Role of Schwann cells in Neural Regeneration Neuroscientist, July 1, 1999; 5(4): 208 - 216. [Abstract] [PDF]

				C. Meier, E. Parmantier, A. Brennan, R. Mirsky, and K. R. Jessen Developing Schwann Cells Acquire the Ability to Survive without Axons by Establishing an Autocrine Circuit Involving Insulin-Like Growth Factor, Neurotrophin-3, and Platelet-Derived Growth Factor-BB J. Neurosci., May 15, 1999; 19(10): 3847 - 3859. [Abstract] [Full Text] [PDF]

				A. M. Brown and G. Lemke Multiple Regulatory Elements Control Transcription of the Peripheral Myelin Protein Zero Gene J. Biol. Chem., November 14, 1997; 272(46): 28939 - 28947. [Abstract] [Full Text] [PDF]

				C. Meisinger, C. Zeschnigk, and C. Grothe In Vivo and in Vitro Effect of Glucocorticoids on Fibroblast Growth Factor (FGF)-2 and FGF Receptor 1Expression J. Biol. Chem., July 12, 1996; 271(28): 16520 - 16525. [Abstract] [Full Text] [PDF]