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1.
Glia ; 60(2): 203-17, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22052506

RESUMEN

Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/deficiencia , Secretasas de la Proteína Precursora del Amiloide/fisiología , Ácido Aspártico Endopeptidasas/deficiencia , Ácido Aspártico Endopeptidasas/fisiología , Vaina de Mielina/metabolismo , Neurregulina-1/metabolismo , Neurregulina-1/fisiología , Procesamiento Proteico-Postraduccional/genética , Transducción de Señal/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/genética , Membrana Celular/genética , Membrana Celular/metabolismo , Técnicas de Cocultivo , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/fisiología , Vaina de Mielina/genética , Neurregulina-1/genética , Péptido Hidrolasas/fisiología , Cultivo Primario de Células , Estructura Terciaria de Proteína/genética
2.
Cell Rep ; 8(4): 1130-45, 2014 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-25131210

RESUMEN

Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.


Asunto(s)
Neurregulina-1/metabolismo , Plasticidad Neuronal , Células Piramidales/fisiología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/fisiología , Movimiento Celular , Condicionamiento Psicológico , Espinas Dendríticas/fisiología , Miedo , Femenino , Expresión Génica , Interneuronas/fisiología , Masculino , Ratones Transgénicos , Red Nerviosa , Neurregulina-1/genética , Transmisión Sináptica
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