The Ras/Raf/ERK Signalling Pathway Drives Schwann Cell Dedifferentiation

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2004 Jul 9

PMID 15241478

Citations 150

Authors

Marie C Harrisingh

Elena Perez-Nadales

David B Parkinson

Denise S Malcolm

Anne W Mudge

Alison C Lloyd

Affiliations

Soon will be listed here.

Abstract

Schwann cells are a regenerative cell type. Following nerve injury, a differentiated myelinating Schwann cell can dedifferentiate and regain the potential to proliferate. These cells then redifferentiate during the repair process. This behaviour is important for successful axonal repair, but the signalling pathways mediating the switch between the two differentiation states remain unclear. Sustained activation of the Ras/Raf/ERK cascade in primary cells results in a cell cycle arrest and has been implicated in the differentiation of certain cell types, in many cases acting to promote differentiation. We therefore investigated its effects on the differentiation state of Schwann cells. Surprisingly, we found that Ras/Raf/ERK signalling drives the dedifferentiation of Schwann cells even in the presence of normal axonal signalling. Furthermore, nerve wounding in vivo results in sustained ERK signalling in associated Schwann cells. Elevated Ras signalling is thought to be important in the development of Schwann cell-derived tumours in neurofibromatosis type 1 patients. Our results suggest that the effects of Ras signalling on the differentiation state of Schwann cells may be important in the pathogenesis of these tumours.

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References

Serrano M, Lin A, McCurrach M, Beach D, Lowe S . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88(5):593-602. DOI: 10.1016/s0092-8674(00)81902-9. View

Ridley A, PATERSON H, Noble M, Land H . Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J. 1988; 7(6):1635-45. PMC: 457147. DOI: 10.1002/j.1460-2075.1988.tb02990.x. View

Bar-Sagi D, Hall A . Ras and Rho GTPases: a family reunion. Cell. 2000; 103(2):227-38. DOI: 10.1016/s0092-8674(00)00115-x. View

Kim H, DeClue J, Ratner N . cAMP-dependent protein kinase A is required for Schwann cell growth: interactions between the cAMP and neuregulin/tyrosine kinase pathways. J Neurosci Res. 1997; 49(2):236-47. View

Maurel P, Salzer J . Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI 3-kinase activity. J Neurosci. 2000; 20(12):4635-45. PMC: 6772460. View

Lamarche N, Tapon N, Stowers L, Burbelo P, Aspenstrom P, BRIDGES T . Rac and Cdc42 induce actin polymerization and G1 cell cycle progression independently of p65PAK and the JNK/SAPK MAP kinase cascade. Cell. 1996; 87(3):519-29. DOI: 10.1016/s0092-8674(00)81371-9. View

Kwon Y, Bhattacharyya A, Alberta J, Giannobile W, Cheon K, Stiles C . Activation of ErbB2 during wallerian degeneration of sciatic nerve. J Neurosci. 1997; 17(21):8293-9. PMC: 6573732. View

Poduslo J, Walikonis R, Domec M, Berg C . The second messenger, cyclic AMP, is not sufficient for myelin gene induction in the peripheral nervous system. J Neurochem. 1995; 65(1):149-59. DOI: 10.1046/j.1471-4159.1995.65010149.x. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

10.

Barbacid M . ras genes. Annu Rev Biochem. 1987; 56:779-827. DOI: 10.1146/annurev.bi.56.070187.004023. View

11.

Monuki E, Weinmaster G, Kuhn R, Lemke G . SCIP: a glial POU domain gene regulated by cyclic AMP. Neuron. 1989; 3(6):783-93. DOI: 10.1016/0896-6273(89)90247-x. View

12.

Sternberg P, Han M . Genetics of RAS signaling in C. elegans. Trends Genet. 1998; 14(11):466-72. DOI: 10.1016/s0168-9525(98)01592-3. View

13.

Lloyd A, Obermuller F, Staddon S, Barth C, McMahon M, Land H . Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev. 1997; 11(5):663-77. DOI: 10.1101/gad.11.5.663. View

14.

Nagarajan R, Svaren J, Le N, Araki T, Watson M, Milbrandt J . EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Neuron. 2001; 30(2):355-68. DOI: 10.1016/s0896-6273(01)00282-3. View

15.

Mitchell P, Perez-Nadales E, Malcolm D, Lloyd A . Dissecting the contribution of p16(INK4A) and the Rb family to the Ras transformed phenotype. Mol Cell Biol. 2003; 23(7):2530-42. PMC: 150721. DOI: 10.1128/MCB.23.7.2530-2542.2003. View

16.

Mathon N, Malcolm D, Harrisingh M, Cheng L, Lloyd A . Lack of replicative senescence in normal rodent glia. Science. 2001; 291(5505):872-5. DOI: 10.1126/science.1056782. View

17.

Roper E, WEINBERG W, Watt F, Land H . p19ARF-independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes. EMBO Rep. 2001; 2(2):145-50. PMC: 1083816. DOI: 10.1093/embo-reports/kve020. View

18.

Zorick T, Syroid D, Brown A, Gridley T, Lemke G . Krox-20 controls SCIP expression, cell cycle exit and susceptibility to apoptosis in developing myelinating Schwann cells. Development. 1999; 126(7):1397-406. DOI: 10.1242/dev.126.7.1397. View

19.

Cichowski K, Jacks T . NF1 tumor suppressor gene function: narrowing the GAP. Cell. 2001; 104(4):593-604. DOI: 10.1016/s0092-8674(01)00245-8. View

20.

Cook S, McCormick F . Inhibition by cAMP of Ras-dependent activation of Raf. Science. 1993; 262(5136):1069-72. DOI: 10.1126/science.7694367. View