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ABSTRACT: Failure of oligodendrocyte precursor cell (OPC) differentiation has been recognized as the leading cause for the failure of myelin regeneration in diseases such as multiple sclerosis (MS). One explanation for the failure of OPC differentiation in MS is the presence of inhibitory molecules in demyelinated lesions. So far only a few inhibitory substrates have been identified in MS lesions. Semaphorin 3A (Sema3A), a secreted member of the semaphorin family, can act as repulsive guidance cue for neuronal and glial cells in the CNS. Recent studies suggest that Sema3A is also expressed in active MS lesions. However, the implication of Sema3A expression in MS lesions remains unclear as OPCs are commonly present in chronic demyelinated lesions. In the present study we identify Sema3A as a potent, selective, and reversible inhibitor of OPC differentiation in vitro. Furthermore, we show that administration of Sema3A into demyelinating lesions in the rat CNS results in a failure of remyelination. Our results imply an important role for Sema3A in the differentiation block occurring in MS lesions.
Journal of Neuroscience 03/2011; 31(10):3719-28. · 7.11 Impact Factor
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ABSTRACT: Schwann cell myelination is tightly regulated by timely expression of key transcriptional regulators that respond to specific environmental cues, but the molecular mechanisms underlying such a process are poorly understood. We found that the acetylation state of NF-κB, which is regulated by histone deacetylases (HDACs) 1 and 2, is critical for orchestrating the myelination program. Mice lacking both HDACs 1 and 2 (HDAC1/2) exhibited severe myelin deficiency with Schwann cell development arrested at the immature stage. NF-κB p65 became heavily acetylated in HDAC1/2 mutants, inhibiting the expression of positive regulators of myelination and inducing the expression of differentiation inhibitors. We observed that the NF-κB protein complex switched from associating with p300 to associating with HDAC1/2 as Schwann cells differentiated. NF-κB and HDAC1/2 acted in a coordinated fashion to regulate the transcriptionally linked chromatin state for Schwann cell myelination. Thus, our results reveal an HDAC-mediated developmental switch for controlling myelination in the peripheral nervous system.
Nature Neuroscience 03/2011; 14(4):437-41. · 15.53 Impact Factor
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Arno Reich,
Christopher Spering,
Karen Gertz,
Christoph Harms,
Ellen Gerhardt,
Golo Kronenberg, Klaus A Nave,
Markus Schwab,
Simone C Tauber,
Anja Drinkut,
Kristian Harms,
Chrstioph P Beier,
Aaron Voigt,
Sandra Göbbels,
Matthias Endres,
Jörg B Schulz
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ABSTRACT: Death receptor (DR) signaling has a major impact on the outcome of numerous neurological diseases, including ischemic stroke. DRs mediate not only cell death signals, but also proinflammatory responses and cell proliferation. Identification of regulatory proteins that control the switch between apoptotic and alternative DR signaling opens new therapeutic opportunities. Fas apoptotic inhibitory molecule 2 (Faim2) is an evolutionary conserved, neuron-specific inhibitor of Fas/CD95-mediated apoptosis. To investigate its role during development and in disease models, we generated Faim2-deficient mice. The ubiquitous null mutation displayed a viable and fertile phenotype without overt deficiencies. However, lack of Faim2 caused an increase in susceptibility to combined oxygen-glucose deprivation in primary neurons in vitro as well as in caspase-associated cell death, stroke volume, and neurological impairment after cerebral ischemia in vivo. These processes were rescued by lentiviral Faim2 gene transfer. In summary, we provide evidence that Faim2 is a novel neuroprotective molecule in the context of cerebral ischemia.
Journal of Neuroscience 01/2011; 31(1):225-33. · 7.11 Impact Factor
