Cell cycle inhibitors p21 and p16 are required for the regulation of Schwann cell proliferation

Atanasoski, Suzana; Boller, Danielle; Ventura, Lukas De; Koegel, Heidi; Boentert, Matthias; Young, Peter; Werner, Sabine; Suter, Ueli

doi:10.1002/glia.20263

Cited by 41 publications

(35 citation statements)

References 35 publications

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“…These combined findings support our previous results (Atanasoski et al, 2002(Atanasoski et al, , 2006) that the molecular control and requirements for proper Schwann cell function differ fundamentally during development and after nerve damage.…”

Section: Discussionsupporting

confidence: 91%

“…During the early postnatal phase, Schwann cell survival and proliferation is regulated, in part, by access to axonally derived neuregulin-1 (Wolpowitz et al, 2000) and axotomyinduced Schwann cell death during development can be rescued by exogenous neuregulin-1 (Grinspan et al, 1996;Trachtenberg and Thompson, 1996). In adult mice, the apoptotic response of Schwann cells after axonal damage is limited (Grinspan et al, 1996;Atanasoski et al, 2006), and neuregulin isoforms are predominantly expressed by Schwann cells (Carroll et al, 1997). These differences might account for the observed discrepancies between neuregulin/erbB functions in development and after nerve injury.…”

Section: Discussionmentioning

confidence: 99%

“…Schwann cell proliferation is independent of cyclin D1 in development, but injury-induced proliferation is strongly impaired in the absence of cyclin D1 (Kim et al, 2000;Atanasoski et al, 2001). Furthermore, the cell cycle inhibitor p21 regulates Schwann cell proliferation in development and after injury by different mechanisms (Atanasoski et al, 2006). Characterizing the molecular signals that control the response of Schwann cells to injury has implications for our understanding of disease mechanisms in inherited and acquired neuropathies (Suter and Scherer, 2003;Berger and Schaumburg, 1995).…”

Section: Introductionmentioning

confidence: 99%

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ErbB2 Signaling in Schwann Cells Is Mostly Dispensable for Maintenance of Myelinated Peripheral Nerves and Proliferation of Adult Schwann Cells after Injury

Atanasoski¹,

Scherer²,

Sirkowski³

et al. 2006

J. Neurosci.

108

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Neuregulin/erbB signaling is critically required for survival and proliferation of Schwann cells as well as for establishing correct myelin thickness of peripheral nerves during development. In this study, we investigated whether erbB2 signaling in Schwann cells is also essential for the maintenance of myelinated peripheral nerves and for Schwann cell proliferation and survival after nerve injury. To this end, we used inducible Cre-loxP technology using a PLP-CreERT2 allele to ablate erbB2 in adult Schwann cells. ErbB2 expression was markedly reduced after induction of erbB2 gene disruption with no apparent effect on the maintenance of already established myelinated peripheral nerves. In contrast to development, Schwann cell proliferation and survival were not impaired in mutant animals after nerve injury, despite reduced levels of MAPK-P (phosphorylated mitogen-activated protein kinase) and cyclin D1. ErbB1 and erbB4 do not compensate for the loss of erbB2. We conclude that adult Schwann cells do not require major neuregulin signaling through erbB2 for proliferation and survival after nerve injury, in contrast to development and in cell culture.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ErbB2 Signaling in Schwann Cells Is Mostly Dispensable for Maintenance of Myelinated Peripheral Nerves and Proliferation of Adult Schwann Cells after Injury

Atanasoski¹,

Scherer²,

Sirkowski³

et al. 2006

J. Neurosci.

108

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“…The right sciatic nerve was exposed at the sciatic notch. The crush was produced by tightly compressing the sciatic nerve at the sciatic notch with flattened forceps (Atanasoski et al, 2001(Atanasoski et al, , 2006a. As opposed to a complete cut, a crush produces degeneration of distal axons, which subsequently regenerate from the proximal segment.…”

Section: Methodsmentioning

confidence: 99%

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Lino¹,

Atanasoski²,

Kvajo³

et al. 2007

J. Neurosci.

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Multiple molecular mechanisms influence nerve regeneration. Because serine proteases were shown to affect peripheral nerve regeneration, we performed nerve crush experiments to study synapse reinnervation in adult mice lacking the serpin protease nexin-1 (PN-1). PN-1 is a potent endogenous inhibitor of thrombin, trypsin, tissue plasminogen activators (tPAs), and urokinase plasminogen activators. Compared with the wild type, a significant delay in synapse reinnervation was detected in PN-1 knock-out (KO) animals, which was associated with both reduced proliferation and increased apoptosis of Schwann cells. Various factors known to affect Schwann cells were also altered. Fibrin deposits, tPA activity, mature BDNF, and the low-affinity p75 neurotrophin receptor were increased in injured sciatic nerves of mutant mice. To test whether the absence of PN-1 in Schwann cells or in the axon caused delay in reinnervation, PN-1 was overexpressed exclusively in the nerves of PN-1 KO mice. Neuronal PN-1 expression did not rescue the delayed reinnervation. The results suggest that Schwann cell-derived PN-1 is crucial for proper reinnervation through its contribution to the autocrine control of proliferation and survival. Thus, the precise balance between distinct proteases and serpins such as PN-1 can modulate the overall impact on the kinetics of recovery.

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“…Expression of p27 is also elevated in quiescent (confluent) cultured rat Schwann cells and in rat sciatic nerve at postnatal day 2 (30). Other CDK inhibitors, p21 and p16, are required for withdrawal from the cell cycle during Schwann cell development (31). We therefore examined the levels of p21 and p27 in D6P2T cells in the presence and absence of db-cAMP and examined the effect of FA2H silencing.…”

Section: Fa2h Silencing Prevents Db-camp-induced Upregulation Of P21 mentioning

confidence: 99%

Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T Schwannoma cells

Alderson

Hama

2009

Journal of Lipid Research

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Sphingolipids are ubiquitous components of eukaryotic cells that regulate various cellular functions. In many cell types, a fraction of sphingolipids contain 2-hydroxy fatty acids, produced by fatty acid 2-hydroxylase (FA2H), as the N-acyl chain of ceramide [hydroxyl fatty acid (hFA)-sphingolipids]. FA2H is highly expressed in myelin-forming cells of the nervous system and in epidermal keratinocytes. While hFA-sphingolipids are thought to enhance the physical stability of specialized membranes produced by these cells, physiological significance of hFA-sphingolipids in many other cell types is unknown. In this study, we report novel roles for FA2H and hFA-sphingolipids in the regulation of the cell cycle. Treatment of D6P2T Schwannoma cells with dibutyrylcAMP (db-cAMP) induced exit from the cell cycle with concomitant upregulation of FA2H. Partial silencing of FA2H in D6P2T cells resulted in 60-70% reduction of hFA-dihydroceramide and hFA-ceramide, with no effect on nonhydroxy dihydroceramide and ceramide. Under these conditions, db-cAMP no longer induced cell cycle exit, and cells continued to grow and divide. Immunoblot analyses revealed that FA2H silencing prevented db-cAMP-induced upregulation of cyclin-dependent kinase inhibitors p21 and p27. These results provide evidence that FA2H is a negative regulator of the cell cycle and facilitates db-cAMP-induced cell cycle exit in D6P2T cells. Sphingolipids are a diverse group of lipids found in all eukaryotic cells. They are major structural components of cell membranes and involved in various cellular functions, such as cell adhesion, signaling, and membrane trafficking (1-3). The structural diversity of sphingolipids arises from .300 distinct carbohydrate head groups as well as modifications on the sphingoid base and the N-acyl chains of ceramide. The sphingoid base in mammalian sphingolipids is predominantly C 18 sphingosine, whereas the N-acyl chains are highly diverse with varying chain length (C 12 -C 34 ), desaturation, and hydroxylation. In mammals, sphingolipids containing 2-hydroxy fatty acids (hFA-sphingolipids) are present at high concentrations in the nervous system, comprising the major myelin lipids galactosylceramide and sulfatide (4). A number of nonneural tissues also contain various hFA-sphingolipids. Examples include hFA-ceramide in the epidermis (5); hFA-sphingomyelin in kidney, intestine, spermatozoa (6-8); and various hFA-glycosphingolipids in liver and intestine (9-12). In addition, aberrant hFAglycosphingolipids are present in various human tumors, including ovarian tumors (13), neuroblastomas (14), small cell lung carcinomas (15), and colon and liver adenocarcinomas (16,17). In some studies, a correlation was reported to exist between hFA-sphingolipid levels and the invasive or drug-resistant nature of tumor cells (18,19). Despite the welldocumented prevalence of hFA-sphingolipids, their specific cellular functions are unknown.The fatty acid 2-hydroxylase FA2H catalyzes the formation of precursors for hFA-sphingolipids, 2-hydroxy...

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Cell cycle inhibitors p21 and p16 are required for the regulation of Schwann cell proliferation

Cited by 41 publications

References 35 publications

ErbB2 Signaling in Schwann Cells Is Mostly Dispensable for Maintenance of Myelinated Peripheral Nerves and Proliferation of Adult Schwann Cells after Injury

ErbB2 Signaling in Schwann Cells Is Mostly Dispensable for Maintenance of Myelinated Peripheral Nerves and Proliferation of Adult Schwann Cells after Injury

Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush

Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T Schwannoma cells

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