Schwann cells and cells in the oligodendrocyte lineage proliferate in response to a 50,000 dalton membrane‐associated mitogen present in developing brain

Nordlund, Michael L.; Hong, Dingming; Fei, Xun; Ratner, Nancy

doi:10.1002/glia.440050304

Cited by 23 publications

(17 citation statements)

References 57 publications

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“…DNA synthesis was measured by monitoring the incorporation of [ 3 H]thymidine into trichloroacetic acid (TCA)-insoluble material by liquid scintillation counting as described (Nordlund et al, 1992).…”

Section: Methodsmentioning

confidence: 99%

Schwann Cell Proliferative Responses to cAMP andNf1Are Mediated by Cyclin D1

Kim¹,

et al. 2001

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In most mammalian cells, the cAMP-dependent protein kinase A pathway promotes growth arrest and cell differentiation. However in Schwann cells, the reverse is true. Elevated levels of cAMP function as the cofactor to a broad range of mitogenic cues in culture and in animals. Previous studies have suggested that cAMP acts at an early point in the Schwann cell mitogenic response, perhaps by stimulating the expression of growth factor receptors. We show here that cAMP acts downstream rather than upstream of growth factor receptor expression. The essential function(s) of cAMP is exerted as Schwann cells progress through the G 1 phase of the cell cycle. Ectopic expression studies using an inducible retroviral vector show that the G 1 phase requirement for cAMP can be alleviated by a single protein, cyclin D1. We show, in addition, that at least one function of the Nf1 tumor suppressor is to antagonize the accumulation of cAMP and the expression of cyclin D1 in Schwann cells. Thus a G 1 phase-specific protein, cyclin D1, accounts for two salient features of Schwann cell growth control: the promitotic response to cAMP and the antimitotic response to the Nf1 tumor suppressor.

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Section: Methodsmentioning

confidence: 99%

Schwann Cell Proliferative Responses to cAMP andNf1Are Mediated by Cyclin D1

Kim¹,

et al. 2001

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“…The Schwann cell labeling index was determined by the percentage of NGFR-positive cells that had incorporated [ 3 H]thymidine in the nucleus. In some experiments, Schwann cell proliferation was tested by using a conventional 96-well plate assay as described previously (47).…”

Section: Methodsmentioning

confidence: 99%

Nf1-Deficient Mouse Schwann Cells Are Angiogenic and Invasive and Can Be Induced To Hyperproliferate: Reversion of Some Phenotypes by an Inhibitor of Farnesyl Protein Transferase

Kim

Ling

Ratner

1997

Molecular and Cellular Biology

135

120

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We have developed a potential model of Schwann cell tumor formation in neurofibromatosis type 1 (NF1). We show that mouse Schwann cells heterozygous or null at Nf1 display angiogenic and invasive properties, mimicking the behavior of Schwann cells from human neurofibromas. Mutations at Nf1 are insufficient to promote Schwann cell hyperplasia. Here we show that Schwann cell hyperplasia can be induced by protein kinase A activation in mutant cells. Removal of serum from the culture medium also stimulates hyperplasia, but only in some mutant cells. After serum removal, clones of hyperproliferating Schwann cells lose contact with axons in vitro, develop growth factor-independent proliferation, and exhibit decreased expression of the cell differentiation marker P0 protein; hyperproliferating cells develop after a 1-week lag in Schwann cells heterozygous at Nf1. The experiments suggest that events subsequent to Nf1 mutations are required for development of Schwann cell hyperplasia. Finally, an anti-Ras farnesyl protein transferase inhibitor greatly diminished both clone formation and hyperproliferation of null mutant cells, but not invasion; farnesyl transferase inhibitors could be useful in treating benign manifestations of NF1.Neurofibromatosis type 1 (NF1) is one of the most common inherited human autosomal dominant diseases, with a worldwide incidence of 1 in 3,500 individuals (56). Benign manifestations frequently associated with NF1 include pigmented lesions of the skin (café au lait spots), hamartomas of the iris (Lisch nodules), learning disabilities, formation of optic pathway gliomas, and neurofibromas (22). Neurofibromas are one of the major defining features of NF1. Cutaneous neurofibromas (benign peripheral nerve sheath tumors) are associated with small nerve branches, plexiform neurofibromas develop along major peripheral nerves, and malignant peripheral nerve sheath tumors (MPNST) develop in about 4% of NF1 patients (56). Genetic studies show that malignant tumors in NF1, including MPNSTs, contain cells with mutations in both the constitutionally inactivated and previously normal somatic allele, consistent with NF1 acting as a tumor suppressor (19,36,64). The mechanism of neurofibroma formation is less clear. While recent studies demonstrated loss of heterozygosity (LOH) at the NF1 locus in some neurofibromas (12, 60), LOH could be associated with either of the major cell types in the benign tumors, fibroblasts or Schwann cells.Schwann cells may be the primary pathogenic cells in neurofibromas. The majority (40 to 85%) of cells in neurofibromas are Schwann cells (18,49), and in contrast to Schwann cells in normal nerve, neurofibroma Schwann cells are found without association with axons (28, 50). Furthermore, in vitro, Schwann cells, but not fibroblasts, from neurofibromas show angiogenic and invasive properties (63). Because the genetic status of neurofibroma Schwann cells is unknown, it remains unclear if a single NF1 mutation is sufficient for manifestation of some neurofibroma Schwann cell phenotype...

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“…Following 18 hr of incubation, cells were pulsed with 0.5 µCi/well [ 3 H]-thymidine for another 24 hr. Schwann cell DNA synthesis was measured by monitoring the incorporation of [ 3 H]-thymidine into trichloroacetic acid-insoluble material by liquid scintillation counting, as described elsewhere (Nordlund et al, 1992). For Schwann cell/DRG cocultures, quiescent Schwann cells (25,000 cells/coverslip) were plated onto rat DRG neurons on collagen-coated coverslips in serumfree defined N2 media.…”

Section: Schwann Cell Proliferation Assaymentioning

confidence: 99%

cAMP-dependent protein kinase A is required for Schwann cell growth: Interactions between the cAMP and neuregulin/tyrosine kinase pathways

1997

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Schwann cell proliferation is stimulated by contact with neurons or exposure to growth factor ligands for tyrosine kinase receptors, effects of which are potentiated by cAMP. Here we show that treatment of rat Schwann cells with recombinant human glial growth factor 2 (rhGGF2), but not with other mitogenic factors, transiently increases intracellular cyclic AMP (cAMP), with maximal elevation at the G0/G1 boundary. The cAMP-dependent protein kinase (PKA) inhibitor H-89 strongly antagonized GGF- and neuron-induced Schwann cell proliferation, with maximum inhibition observed at G0/G1. H-89 also inhibited Schwann cell proliferation induced by growth factors that did not increase intracellular cAMP. Stimulation of Schwann cells with rhGGF2 resulted in 70-fold activation of MAP kinase; forskolin treatment resulted in a 50% decrease in MAP kinase activity but did not alter Raf-1 phosphorylation on Ser-43. These results demonstrate that the MAP kinase cascade represents an intersection between receptor tyrosine kinase and cAMP signaling pathways in Schwann cells and that PKA plays a critical role in Schwann cell cycle progression.

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Schwann cells and cells in the oligodendrocyte lineage proliferate in response to a 50,000 dalton membrane‐associated mitogen present in developing brain

Cited by 23 publications

References 57 publications

Schwann Cell Proliferative Responses to cAMP andNf1Are Mediated by Cyclin D1

Schwann Cell Proliferative Responses to cAMP andNf1Are Mediated by Cyclin D1

Nf1-Deficient Mouse Schwann Cells Are Angiogenic and Invasive and Can Be Induced To Hyperproliferate: Reversion of Some Phenotypes by an Inhibitor of Farnesyl Protein Transferase

cAMP-dependent protein kinase A is required for Schwann cell growth: Interactions between the cAMP and neuregulin/tyrosine kinase pathways

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