RESUMEN
Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.
Asunto(s)
Diferenciación Celular/fisiología , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Cresta Neural/metabolismo , Células-Madre Neurales/metabolismo , Oligodendroglía/metabolismo , Células de Schwann/metabolismo , Animales , Regulación del Desarrollo de la Expresión Génica , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/genética , Ratones , Cresta Neural/citología , Células-Madre Neurales/citología , Oligodendroglía/citología , Factor de Transcripción PAX3 , Factores de Transcripción Paired Box/genética , Factores de Transcripción Paired Box/metabolismo , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismo , Células de Schwann/citologíaRESUMEN
Dicer is responsible for the generation of mature micro-RNAs (miRNAs) and loading them into RNA-induced silencing complex (RISC). RISC functions as a probe that targets mRNAs leading to translational suppression and mRNA degradation. Schwann cells (SCs) in the peripheral nervous system undergo remarkable differentiation both in morphology and gene expression patterns throughout lineage progression to myelinating and nonmyelinating phenotypes. Gene expression in SCs is particularly tightly regulated and critical for the organism, as highlighted by the fact that a 50% decrease or an increase to 150% of normal gene expression of some myelin proteins, like PMP22, results in peripheral neuropathies. Here, we selectively deleted Dicer and consequently gene expression regulation by mature miRNAs from Mus musculus SCs. Our results show that in the absence of Dicer, most SCs arrest at the promyelinating stage and fail to start forming myelin. At the molecular level, the promyelinating transcription factor Krox20 and several myelin proteins [including myelin associated glycoprotein (MAG) and PMP22] were strongly reduced in mutant sciatic nerves. In contrast, the myelination inhibitors SOX2, Notch1, and Hes1 were increased, providing an additional potential basis for impaired myelination. A minor fraction of SCs, with some peculiar differences between sensory and motor fibers, overcame the myelination block and formed unusually thin myelin, in line with observed impaired neuregulin and AKT signaling. Surprisingly, we also found signs of axonal degeneration in Dicer mutant mice. Thus, our data indicate that miRNAs critically regulate Schwann cell gene expression that is required for myelination and to maintain axons via axon-glia interactions.
Asunto(s)
Axones/fisiología , ARN Helicasas DEAD-box/metabolismo , Endorribonucleasas/metabolismo , MicroARNs/metabolismo , Vaina de Mielina/fisiología , Células de Schwann/fisiología , Animales , Axones/ultraestructura , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular/fisiología , ARN Helicasas DEAD-box/deficiencia , ARN Helicasas DEAD-box/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Endorribonucleasas/deficiencia , Endorribonucleasas/genética , Proteínas de Homeodominio/metabolismo , Ratones , Ratones Noqueados , Proteínas de la Mielina/metabolismo , Vaina de Mielina/ultraestructura , Degeneración Nerviosa/metabolismo , Receptor Notch1/metabolismo , Ribonucleasa III , Factores de Transcripción SOXB1/metabolismo , Células de Schwann/ultraestructura , Nervio Ciático/fisiología , Nervio Ciático/ultraestructura , Raíces Nerviosas Espinales/fisiología , Raíces Nerviosas Espinales/ultraestructura , Factor de Transcripción HES-1 , Grabación en VideoAsunto(s)
Neurobiología/historia , Animales , Selección de Profesión , Historia del Siglo XX , Historia del Siglo XXI , SuizaRESUMEN
Jagged1 is a ligand for members of the Notch family of receptors. Mutations in the human JAG1 gene are the major cause of Alagille syndrome, an autosomal dominant disorder affecting the liver, heart, eye, skeleton, kidneys, and craniofacial structures. Although expressed throughout mammalian embryonic development and in the adult, the function of Jagged1 in the central nervous system is not clear. Jagged1 is broadly expressed in the cerebellum suggesting an important role in Notch signaling. In order to address the function of Jagged1 in the mouse central nervous system, we have inactivated the Jag1 gene in the cerebellar primordium at mid-embryogenesis. Loss of Jagged1 results in aberrant granule cell migration and ectopic differentiation in the external germinal layer and molecular layer of the early postnatal cerebellum. We show that Bergmann glia in the cerebellum lose contact to the pial surface and have stunted processes. In vitro analysis revealed a depletion of Bergmann glia in the Jagged1 mutant mice. Our findings suggest that Jagged1 plays a role in cell fate specification and survival in the cerebellum.
Asunto(s)
Proteínas de Unión al Calcio/genética , Diferenciación Celular/genética , Movimiento Celular/genética , Corteza Cerebelosa/embriología , Proteínas de la Membrana/genética , Neuroglía/metabolismo , Neuronas/metabolismo , Animales , Apoptosis/genética , División Celular/genética , Proliferación Celular , Forma de la Célula/genética , Células Cultivadas , Corteza Cerebelosa/citología , Regulación del Desarrollo de la Expresión Génica/genética , Péptidos y Proteínas de Señalización Intercelular , Proteína Jagged-1 , Ratones , Ratones Noqueados , Neuroglía/citología , Neuronas/citología , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Recombinación Genética/genética , Proteínas Serrate-JaggedRESUMEN
Charcot-Marie-Tooth disease (CMT) comprises a family of clinically and genetically very heterogeneous hereditary peripheral neuropathies and is one of the most common inherited neurological disorders. We have generated a mouse model for CMT type 4B1 using embryonic stem cell technology. To this end, we introduced a stop codon into the Mtmr2 locus within exon 9, at the position encoding amino acid 276 of the MTMR2 protein (E276X). Concomitantly, we have deleted the chromosomal region immediately downstream of the stop codon up to within exon 13. The resulting allele closely mimics the mutation found in a Saudi Arabian CMT4B1 patient. Animals homozygous for the mutation showed various degrees of complex myelin infoldings and outfoldings exclusively in peripheral nerves, in agreement with CMT4B1 genetics and pathology. Mainly, paranodal regions of the myelin sheath were affected, with a high degree of quantitative and qualitative variability between individuals. This pathology was progressive with age, and axonal damage was occasionally observed. Distal nerve regions were more affected than proximal parts, in line with the distribution in CMT. However, we found no significant electrophysiological changes, even in aged (16-month-old) mice, suggesting that myelin infoldings and outfoldings per se are not invariably associated with detectable electrophysiological abnormalities. Our animal model provides a basis for future detailed molecular and cellular studies on the underlying disease mechanisms in CMT4B1. Such an analysis will reveal how the disease develops, in particular, the enigmatic myelin infoldings and outfoldings as well as axonal damage, and provide mechanistic insights that may aid in the development of potential therapeutic approaches.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/metabolismo , Modelos Animales de Enfermedad , Ratones , Vaina de Mielina/metabolismo , Nervios Periféricos/patología , Proteínas Tirosina Fosfatasas/genética , Alelos , Animales , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Codón sin Sentido/genética , Electrofisiología , Homocigoto , Humanos , Inmunohistoquímica , Ratones Mutantes Neurológicos , Vaina de Mielina/ultraestructura , Nervios Periféricos/fisiopatología , Proteínas Tirosina Fosfatasas no Receptoras , Eliminación de SecuenciaRESUMEN
Neural stem cells (NSCs) in the postnatal mammalian brain self-renew and are a source of neurons and glia. To date, little is known about the molecular and cellular mechanisms regulating the maintenance and differentiation of these multipotent progenitors. We show that Jagged1 is required by mitotic cells in the subventricular zone (SVZ) and stimulates self-renewal of multipotent epidermal growth factor-dependent NSCs. Jagged1-expressing cells line the adult SVZ and are juxtaposed to Notch1-expressing cells, some of which are putative NSCs. In vitro, endogenous Jagged1 acts through Notch1 to promote NSC maintenance and multipotency. In vivo, reducing Jagged1/Notch1 signaling decreases the number of proliferating cells in the SVZ. In addition, soluble Jagged1 promotes self-renewal and neurogenic potential of multipotent neural progenitors in vitro. Our findings suggest a central role for Jagged1 in the NSC niche in the SVZ for maintaining a population of NSCs in the postnatal brain.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular , Ventrículos Laterales/citología , Proteínas de la Membrana/metabolismo , Células Madre Multipotentes/metabolismo , Transducción de Señal/fisiología , Animales , Factor de Crecimiento Epidérmico/metabolismo , Técnica del Anticuerpo Fluorescente , Péptidos y Proteínas de Señalización Intercelular , Proteína Jagged-1 , Ratones , Células Madre Multipotentes/citología , Receptor Notch1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Serrate-JaggedRESUMEN
Point mutations affecting PMP22 can cause hereditary demyelinating and dysmyelinating peripheral neuropathies. In addition, duplication and deletion of PMP22 are associated with Charcot-Marie-Tooth disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), respectively. This study was designed to elucidate disease processes caused by misexpression of Pmp22 and, at the same time, to gain further information on the controversial molecular function of PMP22. To this end, we took advantage of the unique resource of a set of various Pmp22 mutant mice to carry out comparative expression profiling of mutant and wild-type sciatic nerves. Tissues derived from Pmp22-/- ("knockout"), Pmp22tg (increased Pmp22 copy number), and Trembler (Tr; point mutation in Pmp22) mutant mice were analyzed at two developmental stages: (i) at postnatal day (P)4, when normal myelination has just started and primary causative defects of the mutations are expected to be apparent, and (ii) at P60, with the goal of obtaining information on secondary disease effects. Interestingly, the three Pmp22 mutants exhibited distinct profiles of gene expression, suggesting different disease mechanisms. Increased expression of genes involved in cell cycle regulation and DNA replication is characteristic and specific for the early stage in Pmp22-/- mice, supporting a primary function of PMP22 in the regulation of Schwann cell proliferation. In the Tr mutant, a distinguishing feature is the high expression of stress response genes. Both Tr and Pmp22tg mice show strongly reduced expression of genes important for cholesterol synthesis at P4, a characteristic that is common to all three mutants at P60. Finally, we have identified a number of candidate genes that may play important roles in the disease process or in myelination per se.
Asunto(s)
Dosificación de Gen , Proteínas de la Mielina/genética , Enfermedades del Sistema Nervioso Periférico/genética , Mutación Puntual , Animales , Animales Recién Nacidos , Regulación de la Expresión Génica/genética , Genes cdc/fisiología , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas de la Mielina/biosíntesis , Proteínas de la Mielina/fisiología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patologíaRESUMEN
Jagged1-mediated Notch signaling has been suggested to be critically involved in hematopoietic stem cell (HSC) self-renewal. Unexpectedly, we report here that inducible Cre-loxP-mediated inactivation of the Jagged1 gene in bone marrow progenitors and/or bone marrow (BM) stromal cells does not impair HSC self-renewal or differentiation in all blood lineages. Mice with simultaneous inactivation of Jagged1 and Notch1 in the BM compartment survived normally following a 5FU-based in vivo challenge. In addition, Notch1-deficient HSCs were able to reconstitute mice with inactivated Jagged1 in the BM stroma even under competitive conditions. In contrast to earlier reports, these data exclude an essential role for Jagged1-mediated Notch signaling during hematopoiesis.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular , Células Madre Hematopoyéticas/fisiología , Proteínas de la Membrana/metabolismo , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Animales , Antimetabolitos/administración & dosificación , Antimetabolitos/toxicidad , Médula Ósea/fisiología , Proteínas de Unión al Calcio/deficiencia , Diferenciación Celular/efectos de los fármacos , Fluorouracilo/administración & dosificación , Fluorouracilo/toxicidad , Hematopoyesis/efectos de los fármacos , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/citología , Integrasas/genética , Péptidos y Proteínas de Señalización Intercelular , Proteína Jagged-1 , Proteínas de la Membrana/deficiencia , Ratones , Ratones Transgénicos , Receptores Notch/deficiencia , Proteínas Serrate-Jagged , Transducción de Señal/efectos de los fármacos , Células del Estroma/citología , Células del Estroma/fisiología , Proteínas Virales/genéticaRESUMEN
The myelin and lymphocyte protein (MAL) is a tetraspan raft-associated proteolipid predominantly expressed by oligodendrocytes and Schwann cells. We show that genetic ablation of mal resulted in cytoplasmic inclusions within compact myelin, paranodal loops that are everted away from the axon, and disorganized transverse bands at the paranode--axon interface in the adult central nervous system. These structural changes were accompanied by a marked reduction of contactin-associated protein/paranodin, neurofascin 155 (NF155), and the potassium channel Kv1.2, whereas nodal clusters of sodium channels were unaltered. Initial formation of paranodal regions appeared normal, but abnormalities became detectable when MAL started to be expressed. Biochemical analysis revealed reduced myelin-associated glycoprotein, myelin basic protein, and NF155 protein levels in myelin and myelin-derived rafts. Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes, likely by controlling the trafficking and/or sorting of NF155 and other membrane components in oligodendrocytes.
Asunto(s)
Axones/metabolismo , Sistema Nervioso Central/metabolismo , Microdominios de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas de la Mielina/metabolismo , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Canales de Potasio con Entrada de Voltaje , Proteolípidos/metabolismo , Animales , Axones/patología , Axones/ultraestructura , Moléculas de Adhesión Celular/metabolismo , Comunicación Celular/genética , Sistema Nervioso Central/ultraestructura , Regulación hacia Abajo/genética , Canal de Potasio Kv.1.2 , Microdominios de Membrana/ultraestructura , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Noqueados , Microscopía Electrónica , Proteína Básica de Mielina/metabolismo , Proteínas de la Mielina/genética , Vaina de Mielina/patología , Vaina de Mielina/ultraestructura , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito , Glicoproteína Asociada a Mielina/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Conducción Nerviosa/genética , Oligodendroglía/ultraestructura , Nervio Óptico/metabolismo , Nervio Óptico/patología , Nervio Óptico/ultraestructura , Canales de Potasio/genética , Canales de Potasio/metabolismo , Transporte de Proteínas/genética , Proteolípidos/genética , Nódulos de Ranvier/metabolismo , Nódulos de Ranvier/patología , Nódulos de Ranvier/ultraestructura , Nervio Ciático/metabolismo , Nervio Ciático/patología , Nervio Ciático/ultraestructuraRESUMEN
The reasons for the eventual failure of repair mechanisms in multiple sclerosis are unknown. The presence of precursor and immature oligodendrocytes in some non-repairing lesions suggests a mechanism in which these cells either receive insufficient differentiation signals or are exposed to differentiation inhibitors. Jagged signalling via Notch receptors on oligodendrocyte precursor cells (OPCs) inhibits their differentiation during development and the finding that both notch and jagged are expressed in multiple sclerosis lesions has fostered the view that this signalling pathway may explain remyelination failure. In this study, we show that Notch1 is expressed on adult OPCs and that there are multiple cellular sources of its ligand Jagged1 in a rodent model of remyelination. However, despite their expression, the lesions undergo complete remyelination. To establish whether Notch-jagged signalling regulates the rate of remyelination we compared their expression profiles in young animals with those in older animals, where remyelination occurs more slowly, but could find no correlation between expression and remyelination rate. Finally we found that OPC-targeted Notch1 ablation in cuprizone-treated Plp-creER Notch1(lox/lox) transgenic mice yielded no significant differences in remyelination parameters between knock-out and control mice. Thus, in contrast to developmental myelination, adult expression of Notch1 and Jagged1 neither prevents nor plays a major rate-determining role in remyelination. More generally, the re-expression of developmentally expressed genes following injury in the adult does not per se imply similar function.
Asunto(s)
Encéfalo/inmunología , Proteínas de la Membrana/metabolismo , Esclerosis Múltiple/inmunología , Oligodendroglía/inmunología , Receptores de Superficie Celular/metabolismo , Factores de Transcripción/metabolismo , Envejecimiento/inmunología , Animales , Astrocitos/inmunología , Axones/inmunología , Proteínas de Unión al Calcio , Cerebelo/inmunología , Femenino , Expresión Génica/genética , Péptidos y Proteínas de Señalización Intercelular , Péptidos y Proteínas de Señalización Intracelular , Proteína Jagged-1 , Operón Lac/genética , Macrófagos/inmunología , Proteínas de la Membrana/análisis , Proteínas de la Membrana/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Esclerosis Múltiple/metabolismo , Vaina de Mielina/fisiología , Oligodendroglía/metabolismo , ARN Mensajero/inmunología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Notch1 , Receptores de Superficie Celular/análisis , Receptores de Superficie Celular/inmunología , Rombencéfalo/inmunología , Células de Schwann/inmunología , Proteínas Serrate-Jagged , Células Madre/inmunología , Células Madre/metabolismo , Factores de Transcripción/análisis , Factores de Transcripción/inmunología , Ganglio del Trigémino/inmunologíaRESUMEN
Schwann cells develop from multipotent neural crest stem cells and are important for neuronal survival, maintenance of axonal integrity, and myelination. We used transgenic mice expressing green fluorescent protein in a tissue-specific manner to isolate viable, pure populations of neural crest stem cells and developing Schwann cells, which are not readily accessible by microdissection. Starting with the minute amounts of RNA obtained, a two-round amplification procedure was used to achieve reproducible DNA array hybridizations. We validated our screening procedure by comparisons with the literature and by in situ hybridization. Stage-to-stage comparisons and hierarchical clustering for neural crest and five stages of Schwann cell development suggest a wealth of candidates for genes involved in stem cell regulation and in early Schwann cell development. The combination of methods applied in this study should be generally useful for isolating and profiling other stem cell and difficult to isolate cell populations.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Cresta Neural/citología , Células de Schwann/citología , Células de Schwann/metabolismo , Células Madre/citología , Células Madre/metabolismo , Animales , Recuento de Células , Diferenciación Celular/fisiología , Linaje de la Célula/genética , Separación Celular/métodos , Células Cultivadas , Citometría de Flujo , Genes Reporteros , Edad Gestacional , Proteínas Fluorescentes Verdes , Hibridación in Situ , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Ratones , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Valor Predictivo de las Pruebas , ARN/química , ARN/aislamiento & purificación , Reproducibilidad de los ResultadosRESUMEN
The demyelinating toxin cuprizone is used increasingly in mouse studies of central nervous system remyelination. The value of this model for such studies depends on an accurate description of its quantifiable features. We therefore investigated histology and ultrastructure during the early oligodendrocyte differentiation phase of remyelination in mice given cuprizone and allowed to recover for 2 weeks. Limiting the dose of cuprizone to 0.2% overcame significant mouse morbidity and weight loss seen with a 0.4% dose, but the distribution of cuprizone-induced demyelination was anatomically variable. The caudal corpus callosum and dorsal hippocampal commissure mostly demyelinated at this dose, but the rostral corpus callosum and rostral cerebellar peduncles did not. This variable response, together with small axon diameters and hence thin myelin sheaths, hindered analysis of the progress of early remyelination. The proportion of myelinated and unmyelinated axons in defined regions followed expected trends, but there was pronounced variation between animals. Furthermore, group mean G ratios did not change as expected during the early stages of remyelination, and regression analysis revealed a complex relationship between axon diameter and myelin sheath thickness during this period. We also noted axonal pathology that persisted for at least 2 weeks after cuprizone withdrawal.
Asunto(s)
Cuerpo Calloso/patología , Enfermedades Desmielinizantes/fisiopatología , Hipocampo/patología , Vaina de Mielina/metabolismo , Animales , Axones/metabolismo , Axones/patología , Quelantes , Cuerpo Calloso/metabolismo , Cuerpo Calloso/ultraestructura , Cuprizona , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/ultraestructura , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/ultraestructura , Prosencéfalo/metabolismo , Prosencéfalo/patología , Análisis de Regresión , Caracteres Sexuales , Factores de TiempoRESUMEN
The L2/HNK-1 carbohydrate is carried by many neural recognition molecules and is involved in neural cell interactions during development, regeneration in the peripheral nervous system, synaptic plasticity, and autoimmune-based neuropathies. Its key structure consists of a sulfated glucuronic acid linked to lactosaminyl residues. Because of its biological importance but limited availability, the phage display method was used to isolate a collection of peptide mimics that bind specifically to an L2/HNK-1 antibody. The phages isolated from a 15-mer peptide library by adsorption to this antibody share a consensus sequence of amino acids. The peptide mimicked several important functions of the L2/HNK-1 carbohydrate, such as binding to motor neurons in vitro, and preferential promotion of in vitro neurite outgrowth from motor axons compared with sensory neurons. A scrambled version of the peptide had no activity. The combined observations indicate that we have isolated a mimic of the L2/HNK-1 carbohydrate that is able to act as its functional substitute.
Asunto(s)
Antígenos CD57/química , Carbohidratos/química , Epítopos/química , Imitación Molecular/fisiología , Péptidos/química , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/química , Antígenos de Superficie/química , Antígenos de Superficie/inmunología , Unión Competitiva/fisiología , Antígenos CD57/inmunología , Secuencia de Carbohidratos , Carbohidratos/inmunología , Células Cultivadas , Embrión de Pollo , Epítopos/inmunología , Ganglios Espinales/citología , Ganglios Espinales/efectos de los fármacos , Glucolípidos/química , Glucolípidos/inmunología , Datos de Secuencia Molecular , Neuronas Motoras/citología , Neuronas Motoras/efectos de los fármacos , Neuritas/efectos de los fármacos , Neuronas Aferentes/citología , Neuronas Aferentes/efectos de los fármacos , Biblioteca de Péptidos , Péptidos/inmunología , Péptidos/farmacología , Unión Proteica/fisiología , Especificidad por Sustrato/fisiologíaRESUMEN
We have selectively inhibited Notch1 signaling in oligodendrocyte precursors (OPCs) using the Cre/loxP system in transgenic mice to investigate the role of Notch1 in oligodendrocyte (OL) development and differentiation. Early development of OPCs appeared normal in the spinal cord. However, at embryonic day 17.5, premature OL differentiation was observed and ectopic immature OLs were present in the gray matter. At birth, OL apoptosis was strongly increased in Notch1 mutant animals. Premature OL differentiation was also observed in the cerebrum, indicating that Notch1 is required for the correct spatial and temporal regulation of OL differentiation in various regions of the central nervous system. These findings establish a widespread function of Notch1 in the late steps of mammalian OPC development in vivo.