RESUMEN
The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized. Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models. We find that loss of SNF5 phenocopies ß-catenin hyperactivation and that SNF5 is essential for regulating Wnt/ß-catenin pathway target expression. These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Genes Supresores de Tumor , Factores de Transcripción/genética , Vía de Señalización Wnt , Animales , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proteínas Cromosómicas no Histona/deficiencia , Proteínas de Unión al ADN/deficiencia , Regulación Neoplásica de la Expresión Génica , Humanos , Meduloblastoma/genética , Ratones , Ratones Transgénicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Tumor Rabdoide , Proteína SMARCB1 , Factor de Transcripción 4 , Factores de Transcripción/deficiencia , Factores de Transcripción/metabolismo , Transcriptoma , Células Tumorales CultivadasAsunto(s)
Craneofaringioma/patología , Craneofaringioma/cirugía , Melatonina/deficiencia , Complicaciones Posoperatorias/metabolismo , Trastornos del Sueño del Ritmo Circadiano/etiología , Trastornos del Sueño del Ritmo Circadiano/metabolismo , Adolescente , Factores de Edad , Biomarcadores/análisis , Biomarcadores/metabolismo , Ritmo Circadiano/fisiología , Femenino , Humanos , Hipopituitarismo/etiología , Hipopituitarismo/fisiopatología , Masculino , Melatonina/metabolismo , Melatonina/uso terapéutico , Procedimientos Neuroquirúrgicos/efectos adversos , Obesidad Mórbida/complicaciones , Obesidad Mórbida/etiología , Fototerapia/normas , Glándula Pineal/metabolismo , Complicaciones Posoperatorias/fisiopatología , Sueño/fisiología , Trastornos del Sueño del Ritmo Circadiano/fisiopatología , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiopatología , Núcleo Supraquiasmático/cirugía , Adulto JovenRESUMEN
OBJECTIVE: To study the risk factors for the development of moyamoya syndrome after cranial irradiation for primary brain tumors in children. METHODS: We reviewed neuroimaging studies and dosimetry data for 456 children who were treated with radiation for a primary brain tumor and who were prospectively evaluated with serial neuroimaging studies and neurologic evaluations. A total of 345 patients had both adequate neuroimaging and radiation dosimetry data for further analysis. We used survival analysis techniques to examine the relationship of clinically important variables as risk factors for the development of moyamoya over time. RESULTS: Overall, 12 patients (3.5%) developed evidence of moyamoya. The onset of moyamoya was more rapid for patients with neurofibromatosis type 1 (NF1) (median of 38 vs 55 months) and for patients who received >5,000 cGy of radiation (median of 42 vs 67 months). In a multiple Cox proportional hazards regression analysis controlling for age at start of radiation, each 100-cGy increase in radiation dose increased the rate of moyamoya by 7% (hazard ratio [HR] = 1.07, 95% CI: 1.02 to 1.13, p = 0.01) and the presence of NF1 increased the rate of moyamoya threefold (HR = 3.07, 95% CI: 0.90 to 10.46, p = 0.07). CONCLUSIONS: Moyamoya syndrome is a potentially serious complication of cranial irradiation in children, particularly for those patients with tumors in close proximity to the circle of Willis, such as optic pathway glioma. Patients who received higher doses of radiation to the circle of Willis and with neurofibromatosis type 1 have increased risk of the development of moyamoya syndrome.
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Neoplasias Encefálicas/radioterapia , Arterias Cerebrales/efectos de la radiación , Enfermedad de Moyamoya/epidemiología , Traumatismos por Radiación/epidemiología , Radioterapia/efectos adversos , Boston/epidemiología , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Niño , Preescolar , Círculo Arterial Cerebral/patología , Círculo Arterial Cerebral/fisiopatología , Círculo Arterial Cerebral/efectos de la radiación , Comorbilidad , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Incidencia , Lactante , Masculino , Neurofibromatosis 1/radioterapia , Quiasma Óptico/patología , Quiasma Óptico/fisiopatología , Quiasma Óptico/efectos de la radiación , Estudios Prospectivos , Factores de Riesgo , Análisis de SupervivenciaAsunto(s)
Meningitis Bacterianas/complicaciones , Enfermedad Aguda , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Examen Neurológico , Núcleo Familiar , Estudios Prospectivos , Psicometría , TiempoRESUMEN
Pheochromocytomas are neural crest-derived tumors that occur mostly sporadically, but may also be part of inherited syndromes. The molecular pathogenesis of sporadic pheochromocytomas remains unknown. Recently, the susceptibility gene for familial paraganglioma syndrome, a disorder embryologically related to pheochromocytomas, was characterized and shown to encode the small subunit of succinate dehydrogenase (SDHD), which is part of the mitochondrial complex II. This complex regulates oxygen-sensing signals. Importantly, hypoxic signals also appear to be related to the pathogenesis of pheochromocytomas associated with von Hippel-Lindau syndrome. We sequenced the entire coding region of the SDHD gene in a series of pheochromocytomas. Although we did not find mutations in the gene, we identified a new intronic single nucleotide polymorphism in 15% of the samples (g.97739A-->G). We also confirmed the existence of a sequence highly homologous to the SDHD complementary DNA in chromosome 1p34--36, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of our samples that was also present in the germline. This sequence does not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this series of sporadic pheochromocytomas. The existence of SDHD pseudogenes should be considered when analyzing complementary DNA-based samples.
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Neoplasias de las Glándulas Suprarrenales/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de la Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Secuencia de Aminoácidos/genética , Secuencia de Bases/genética , Cromosomas Humanos Par 1/genética , Humanos , Datos de Secuencia Molecular , Polimorfismo Genético/genética , Seudogenes/genética , Succinato Deshidrogenasa , Síndrome , Transcripción GenéticaRESUMEN
OBJECTIVE: To describe neuropsychological functioning (with a specific focus on cognition and memory) after surgical treatment of craniopharyngiomas. METHODS: Sixteen patients who were between 6 and 15 years of age at the time of surgery comprised the sample. Each child had been treated for a craniopharyngioma with surgery only, on Dana-Farber Cancer Institute Protocol 92-077. RESULTS: The overall level of cognitive functioning was well within the average range, with both language and visuospatial functioning being generally intact; however, specific memory problems, in both the language and visuospatial domains, were evident. CONCLUSION: Although general cognitive functioning was intact after the surgical treatment of craniopharyngiomas, difficulties in the retrieval of learned information were observed. Neuropsychological assessments, with a focus on memory recall, should be a component of the medical management plan for each child.
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Craneofaringioma/cirugía , Trastornos de la Memoria/diagnóstico , Pruebas Neuropsicológicas , Neoplasias Hipofisarias/cirugía , Complicaciones Posoperatorias/diagnóstico , Adolescente , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Trastornos de la Memoria/psicología , Complicaciones Posoperatorias/psicologíaRESUMEN
BACKGROUND AND OBJECTIVES: The postoperative cerebellar mutism syndrome (CMS) is an unique acute postoperative complication characterized by transient decrease in speech output (often mutism), apathy, irritability as well as global cerebellar dysfunction. As much as 25% of patients undergoing a resection of a cerebellar or IV ventricular tumor may develop such a syndrome. In this retrospective study we characterize the clinical features of the CMS and explore potential etiologic mechanisms. METHODS: We conducted a retrospective analysis of medical records and imaging tests of 8 consecutive patients with the CMS identified through the database of the Children's Hospital and Dana-Farber Cancer Institute, Boston, and compared with a control group of 8 unaffected children undergoing a comparable tumor resection. RESULTS: In contrast to the control group, children in the affected group had marked decrease in speech output and comprehension, apathy and lack of initiative, inattention, persistent eye closure, flaccid hemiparesis and a severe global cerebellar dysfunction. Swallowing difficulties and bowel and bladder dysfunction were also observed. The median duration of the syndrome as judged by the persistence of the communication abnormalities was 4 weeks. The recovery was near complete with exception for a persistent global cerebellar dysfunction. A comparison of CT and MRI scans of children in both groups failed to identify distinguishing features. CONCLUSION: A surgical lesion of the midline cerebellum can cause a complex neurological dysfunction such as the CMS. Thus, we postulate that the cerebellum and its connections function as a 'modulatory system' in control of both motor and non-motor functions, including attention and language.
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Mutismo Acinético/etiología , Neoplasias Cerebelosas/cirugía , Meduloblastoma/cirugía , Complicaciones Posoperatorias , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
An elevation in the circulating level of the squamous-cell carcinoma antigen (SCCA) can be a poor prognostic indicator in certain types of squamous-cell cancers. Total SCCA in the circulation comprises 2 nearly identical, approximately 45 kDa proteins, SCCA1 and SCCA2. Both proteins are members of the high-molecular weight serine proteinase inhibitor (serpin) family with SCCA1 paradoxically inhibiting lysosomal cysteine proteinases and SCCA2 inhibiting chymotrypsin-like serine proteinases. Although SCCA1 and SCCA2 are detected in the cytoplasm of normal squamous epithelial cells, neither serpin is detected normally in the serum. Thus, their presence in the circulation at relatively high concentrations suggests that malignant epithelial cells are re-directing serpin activity to the fluid phase via an active secretory process. Because serpins typically inhibit their targets by binding at 1:1 stoichiometry, a change in the distribution pattern of SCCA1 and SCCA2 (i.e., intracellular to extracellular) could indicate the need of tumor cells to neutralize harmful extracellular proteinases. The purpose of our study was to determine experimentally the fate of SCCA1 and SCCA2 in squamous carcinoma cells. Using subcellular fractionation, SCCA-green fluorescent fusion protein expression and confocal microscopy, SCCA1 and SCCA2 were found exclusively in the cytosol and were not associated with nuclei, mitochondria, lysosomes, microtubules, actin or the Golgi. In contrast to previous reports, metabolic labeling and pulse-chase experiments showed that neither non-stimulated nor TNFalpha/PMA-stimulated squamous carcinoma cells appreciably secreted these ov-serpins into the medium. Collectively, these data suggest that the major site of SCCA1 and SCCA2 inhibitory activity remains within the cytosol and that their presence in the sera of patients with advanced squamous-cell carcinomas may be due to their passive release into the circulation.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Serpinas/metabolismo , Secuencia de Aminoácidos , Animales , Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Células COS , Citosol/metabolismo , Endopeptidasas/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Datos de Secuencia Molecular , Inhibidores de Proteasas/sangre , Inhibidores de Proteasas/metabolismo , Homología de Secuencia de Aminoácido , Serpinas/sangre , Fracciones Subcelulares/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/farmacología , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/metabolismoRESUMEN
Differentiation of neurons within the central nervous system occurs by the combined effects of intrinsic genetic programs and epigenetic stimuli. Disorders causing mental retardation and other abnormalities of higher cortical function arise by disturbances of the normal developmental sequence. MRDD Research Reviews 6:41-46, 2000.
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Sistema Nervioso Central/embriología , Sistema Nervioso Central/crecimiento & desarrollo , Malformaciones del Sistema Nervioso/embriología , Animales , Desarrollo Embrionario y Fetal , Crecimiento , Humanos , Malformaciones del Sistema Nervioso/fisiopatologíaRESUMEN
Sciatic nerve axons in cyclin D1 knockout mice develop normally, become properly ensheathed by Schwann cells, and appear to function normally. However, in the Wallerian degeneration model of nerve injury, the mitotic response of Schwann cells is completely inhibited. The mitotic block is Schwann cell autonomous and developmentally regulated. Rescue analysis (by "knockin" of cyclin E) indicates that D1 protein, rather than regulatory elements of the D1 gene, provides the essential Schwann cell function. Genetic inhibition of the Schwann cell cycle shows that neuronal responses to nerve injury are surprisingly independent of Schwann cell mitotic responses. Even axonal regrowth into the distal zone of a nerve crush injury is not markedly impaired in cyclin D1-/- mice.
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Ciclina D1/fisiología , Regulación del Desarrollo de la Expresión Génica , Genes de Cambio/fisiología , Regeneración Nerviosa/fisiología , Células de Schwann/fisiología , Animales , División Celular/fisiología , Células Cultivadas , Senescencia Celular/fisiología , Ciclina D1/deficiencia , Ciclina D1/genética , Ciclina E/genética , Ciclina E/fisiología , Ganglios Espinales/citología , Ganglios Espinales/embriología , Ratones , Ratones Noqueados/genética , Mitosis , Fenotipo , Ratas , Valores de Referencia , Células de Schwann/patología , Degeneración Walleriana/patologíaRESUMEN
Medulloblastoma is the most common malignant embryonic tumors of the central nervous system. The nevoid basal cell carcinoma syndrome (NBCCS), which is caused by mutations of PTCH gene on chromosome 9q22, accounts for about 2% of all medulloblastomas. Previous studies of PTCH in sporadic medulloblastomas using single strand conformational polymorphism (SSCP) detected mutations in about 10% of the tumors. In this study, we directly sequenced the PTCH gene in 20 sporadic medulloblastoma DNA samples. A nonsense mutation (Q694X) and a splice site alteration (2875+1G>A) were identified in two of the samples. The mutations are predicted to result in a truncated PTCH protein and aberrant splicing, respectively. In both cases, only the mutant alleles were identified, indicating that the mutations were associated with loss of the wild-type PTCH allele in the tumor cells. Several novel variants, including 1653T>C, 1672C>T, and 2292C>T, were also found in these tumor samples. One of the two mutations detected in this study had been missed by SSCP, suggesting that the true rate of PTCH mutations in sporadic medulloblastomas may be underestimated by SSCP screening. Nevertheless, the frequency of mutations in this study did not differ from previous reports.
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Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Proteínas de la Membrana/genética , Mutación/genética , Humanos , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular , Análisis de Secuencia de ADN/métodos , Células Tumorales CultivadasRESUMEN
Target-derived neurotrophins initiate signals that begin at nerve terminals and cross long distances to reach the cell bodies and regulate gene expression. Neurotrophin receptors, Trks, themselves serve as retrograde signal carriers. However, it is not yet known whether the retrograde propagation of Trk activation reflects movement of Trk receptors from neurites to cell bodies or reflects serial activation of stationary Trk molecules. Here, we show that neurotrophins selectively applied to distal neurites of sensory neurons rapidly induce phosphorylation of the transcription factor cAMP response element-binding protein (CREB) and also cause a slower increase in Fos protein expression. Both nuclear responses require activation of neurotrophin receptors (Trks) at distal nerve endings and retrograde propagation of Trk activation to the nerve cell bodies. Using photobleach and recovery techniques to follow biologically active, green fluorescent protein (GFP)-tagged BDNF receptors (TrkB-GFP) in live cells during retrograde signaling, we show that TrkB-GFP moves rapidly from neurites to the cell bodies. This rapid movement requires ligand binding, Trk kinase activity, and intact axonal microtubules. When they reach the cell bodies, the activated TrkB receptors are in a complex with ligand. Thus, the retrograde propagation of activated TrkB from neurites to cell bodies, although rapid, reflects microtubule-dependent transport of phosphorylated Trk-ligand complexes. Moreover, the relocation of activated Trk receptors from nerve endings to cell bodies is required for nuclear signaling responses. Together, these data support a model of retrograde signaling whereby rapid vesicular transport of ligand-receptor complex from the neurites to the cell bodies mediates the nuclear responses.
Asunto(s)
Núcleo Celular/fisiología , Ganglios Espinales/fisiología , Factores de Crecimiento Nervioso/farmacología , Neuritas/fisiología , Neuronas/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores de Factor de Crecimiento Nervioso/fisiología , Transducción de Señal , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Núcleo Celular/efectos de los fármacos , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ganglios Espinales/citología , Células HeLa , Humanos , Neuronas/citología , Neuronas/efectos de los fármacos , Fosforilación , Proteínas Tirosina Quinasas Receptoras/genética , Receptor de Factor Neurotrófico Ciliar , Receptores de Factor de Crecimiento Nervioso/genética , Proteínas Recombinantes de Fusión/metabolismo , Transcripción Genética , TransfecciónRESUMEN
The authors describe a 7-year-old Chinese-American female with a germinoma of the basal ganglia who presented with progressive hemiparesis and cerebral hemiatrophy. The additional finding of markedly elevated antiphospholipid antibodies suggests the possibility of an autoimmune pathogenesis for the progressive cerebral atrophy, as well as the later development of cognitive decline, tics, and obsessive-compulsive behaviors.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Germinoma/diagnóstico , Anticuerpos Antifosfolípidos/análisis , Atrofia/etiología , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/etiología , Encéfalo/patología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/radioterapia , Niño , Femenino , Germinoma/complicaciones , Germinoma/radioterapia , Hemiplejía/etiología , Humanos , Imagen por Resonancia Magnética , Radioterapia/métodos , Tomografía Computarizada de Emisión de Fotón Único , Resultado del TratamientoRESUMEN
Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome. Here, we provide evidence that TrkC is more than simply a passive marker of prognosis. We demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in the presence of NT-3; (b) overexpression of TrkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c) trkC expression by individual tumor cells is highly correlated with apoptosis within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling promotes apoptosis by activating multiple parallel signaling pathways and by inducing immediate-early gene expression of both c-jun and c-fos. Considered collectively, these results support the conclusion that the biological actions of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth through the promotion of apoptosis.
Asunto(s)
Apoptosis/fisiología , Meduloblastoma/patología , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores de Factor de Crecimiento Nervioso/fisiología , Animales , Apoptosis/efectos de los fármacos , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Preescolar , Activación Enzimática , Femenino , Humanos , Lactante , Masculino , Meduloblastoma/enzimología , Meduloblastoma/ultraestructura , Ratones , Ratones Desnudos , Factores de Crecimiento Nervioso/farmacología , Neurotrofina 3 , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor trkC , Receptores de Factor de Crecimiento Nervioso/biosíntesis , Receptores de Factor de Crecimiento Nervioso/metabolismo , Transducción de Señal/fisiología , Estimulación Química , Células Tumorales CultivadasRESUMEN
We used anti-phosphopeptide-immunodetecting antibodies as immunohistochemical reagents to define the location and activity state of p185(erbB2) during Wallerian degeneration. Nerve damage induces a phosphorylation event at Y1248, a site that couples p185(erbB2) to the Ras-Raf-MAP kinase signal transduction pathway. Phosphorylation of p185(erbB2) occurs within Schwann cells and coincides in time and space with Schwann cell mitotic activity, as measured by bromodeoxyuridine uptake. These visual images of receptor autophosphorylation link activation of p185(erbB2) to the Schwann cell proliferation that accompanies nerve regeneration.
Asunto(s)
Regulación de la Expresión Génica , Proto-Oncogenes , Receptor ErbB-2/biosíntesis , Nervio Ciático/fisiología , Degeneración Walleriana/genética , Animales , Anticuerpos Monoclonales/inmunología , Bromodesoxiuridina/análisis , Proteínas Quinasas Dependientes de Calcio-Calmodulina/fisiología , Línea Celular , Fibroblastos , Inmunohistoquímica , Masculino , Ratones , Fosforilación , Fosfotirosina/inmunología , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas c-raf/fisiología , Ratas , Ratas Sprague-Dawley , Receptor ErbB-2/genética , Células de Schwann/metabolismo , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Transducción de Señal/fisiologíaRESUMEN
During development target-derived neurotrophins promote the survival of neurons. However, mature neurons no longer depend on the target for survival. Do target-derived neurotrophins retain retrograde signaling functions in mature neurons, and, if so, how are they executed? We addressed this question by using a phosphotyrosine-directed antibody to locate activated Trk receptors in adult rat sciatic nerve. We show that catalytically active Trk receptors are located within the axon of adult rat sciatic nerve and that they are distributed throughout the length of the axons. These catalytically active receptors are phosphorylated on tyrosine at a position that couples them to the signal-generating proteins Ras and PI3 kinase. Neurotrophin applied at sciatic nerve terminals increases both catalytic activity and phosphorylation state of Trk receptors at distant points within the axons. Trk activation initiated at the nerve terminals propagates through the axon toward the nerve cell body at an initial rate that exceeds that of conventional vesicular transport. However, our data suggest that this rapid signal is nevertheless vesicle-associated. Thus, in mature nerves, activated Trk receptors function as rapid retrograde signal carriers to execute remote responses to target-derived neurotrophins.
Asunto(s)
Transporte Axonal/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores de Factor de Crecimiento Nervioso/fisiología , Transducción de Señal/fisiología , Células 3T3 , Acetilación , Animales , Anticuerpos/inmunología , Transporte Axonal/efectos de los fármacos , Sitios de Unión , Factor Neurotrófico Derivado del Encéfalo/farmacología , Catálisis , Masculino , Ratones , Fosfopéptidos/inmunología , Ratas , Ratas Sprague-Dawley , Receptor trkA , Receptor trkB , Receptor trkC , Transducción de Señal/efectos de los fármacos , Dominios Homologos src/inmunologíaRESUMEN
While target-derived neurotrophins are required for the survival of developing neurons in the PNS, the functions of neurotrophins in the CNS are unclear. Mice with a targeted gene deletion of brain-derived neurotrophic factor (BDNF) exhibit a wide-based gait. Consistent with this behavioral evidence of cerebellar dysfunction, there is increased death of granule cells, stunted growth of Purkinje cell dendrites, impaired formation of horizontal layers, and defects in the rostral-caudal foliation pattern. These abnormalities are accompanied by decreased Trk activation in granule and Purkinje cells of mutant animals, indicating that both cell types are direct targets for BDNF. These data suggest that BDNF acts as an anterograde or an autocrine-paracrine factor to regulate survival and morphologic differentiation of developing CNS neurons, and thereby affects neural patterning.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/fisiología , Sistema Nervioso Central/crecimiento & desarrollo , Cerebelo/crecimiento & desarrollo , Mutación/genética , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Cerebelo/metabolismo , Inmunohistoquímica , Ratones , Ratones MutantesRESUMEN
Medulloblastomas may be derived from granule cells of the developing cerebellum. Children with tumors expressing high levels of the neurotrophin-3 receptor, TrkC, have a more favorable outcome. During development, TrkC is expressed in the most mature granule cells. Favorable medulloblastomas may be derived from more highly differentiated granule cells.
Asunto(s)
Neoplasias Cerebelosas/fisiopatología , Cerebelo/citología , Cerebelo/crecimiento & desarrollo , Meduloblastoma/fisiopatología , Factores de Crecimiento Nervioso/fisiología , Animales , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Gránulos Citoplasmáticos/efectos de los fármacos , Humanos , Meduloblastoma/genética , Meduloblastoma/patología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/biosíntesis , Proteínas Tirosina Quinasas Receptoras/genética , Receptor trkA , Receptores de Factor de Crecimiento Nervioso/biosíntesis , Receptores de Factor de Crecimiento Nervioso/genéticaRESUMEN
We have examined the postnatal development of satellite cells associated with parasympathetic neurons of mouse salivary duct ganglia. The number of satellite cells associated with each neuron was found to increase during the first 8 weeks after birth but remained constant thereafter. This corresponds to the period of maximal growth of the salivary gland that serves as the target organ innervated by these neurons. At all ages examined, the number of satellite cells associated with each neuron was found to be highly correlated with neuronal volume. The development of satellite cells associated with individual identified neurons was followed directly by in vivo video microscopy over several months, and the number of satellite cell nuclei was found to increase in regions of the neuronal surface with increasing numbers of synaptic boutons. These results indicate that the postnatal addition of satellite cells to parasympathetic neurons is linked to neuronal enlargement and that synaptic remodeling occurs in concert with satellite cell development.
Asunto(s)
Neuroglía/citología , Neuronas/citología , Sistema Nervioso Parasimpático/crecimiento & desarrollo , Animales , Recuento de Células , Núcleo Celular/ultraestructura , Tamaño de la Célula , Masculino , Ratones , Ratones Endogámicos , Sistema Nervioso Parasimpático/citología , Distribución de PoissonRESUMEN
BACKGROUND: Stereotactic radiotherapy (SRT) is fractionated radiotherapy delivered under stereotactic guidance to produce highly focal and precise therapy. We studied the incidence of imaging changes that can mimic tumor progression after completion of SRT for childhood low grade astrocytoma. METHODS: Between June 1992 and September 1994, we prospectively treated 28 children with low grade astrocytomas with SRT. The patients ranged in age from 2 to 22 years (median: 10 yrs) and none had received prior radiation therapy or radiosurgery. Routine fractionation was employed (180-200 centigray[cGy]) to a total dose of 5220-6000 cGy over 5 to 6 weeks. All of the patients underwent initial and follow-up magnetic resonance imaging (MRI) according to protocol. RESULTS: Median clinical follow-up for the 28 patients was 24 months (range, 5-32 mos) with a median radiographic follow-up of 15 months (range, 3-26 mos). Fifteen patients had reduction in tumor size, one patient had stable disease. Twelve patients (43%) developed increased size of the lesion, increased signal intensity or enhancement, cysts or cavitations, and an increase in edema or mass effect on follow-up MRI. Most of these changes occurred between 9 and 12 months after the start of SRT and resolved or decreased by 15 to 21 months. All but one patient had normal or stable neurologic examinations. CONCLUSIONS: Treatment-related MRI changes are common after conventionally fractionated schedules using stereotactic radiation techniques for patients with low grade astrocytomas. These changes can be distinguished from tumor progression by their transient nature as well as the general absence of clinical symptoms.