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1.
Transl Psychiatry ; 6(11): e934, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27801899

RESUMEN

Given the complexity and heterogeneity of the genomic architecture underlying schizophrenia, molecular analyses of these patients with defined and large effect-size genomic defects could provide valuable clues. We established human-induced pluripotent stem cells from two schizophrenia patients with the 22q11.2 deletion (two cell lines from each subject, total of four cell lines) and three controls (total of four cell lines). Neurosphere size, neural differentiation efficiency, neurite outgrowth, cellular migration and the neurogenic-to-gliogenic competence ratio were significantly reduced in patient-derived cells. As an underlying mechanism, we focused on the role of DGCR8, a key gene for microRNA (miRNA) processing and mapped in the deleted region. In mice, Dgcr8 hetero-knockout is known to show a similar phenotype of reduced neurosphere size (Ouchi et al., 2013). The miRNA profiling detected reduced expression levels of miRNAs belonging to miR-17/92 cluster and miR-106a/b in the patient-derived neurospheres. Those miRNAs are reported to target p38α, and conformingly the levels of p38α were upregulated in the patient-derived cells. p38α is known to drive gliogenic differentiation. The inhibition of p38 activity by SB203580 in patient-derived neurospheres partially restored neurogenic competence. Furthermore, we detected elevated expression of GFAP, a gliogenic (astrocyte) marker, in postmortem brains from schizophrenia patients without the 22q11.2 deletion, whereas inflammation markers (IL1B and IL6) remained unchanged. In contrast, a neuronal marker, MAP2 expressions were decreased in schizophrenia brains. These results suggest that a dysregulated balance of neurogenic-to-gliogenic competence may underlie neurodevelopmental disorders such as schizophrenia.


Asunto(s)
Síndrome de Deleción 22q11/genética , Células Madre Pluripotentes/metabolismo , Esquizofrenia/genética , Síndrome de Deleción 22q11/patología , Adolescente , Adulto , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Casos y Controles , Línea Celular , Variaciones en el Número de Copia de ADN , Femenino , Tamización de Portadores Genéticos , Heterogeneidad Genética , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , MicroARNs/genética , Neuronas , Fenotipo , Células Madre Pluripotentes/patología , Proteínas de Unión al ARN/genética , Esquizofrenia/patología
2.
No To Hattatsu ; 33(2): 114-20, 2001 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-11260912

RESUMEN

Self-renewing and multipotent neural stem cells are present in the adult human brain. We successfully harvested neural stem cells from mice and humans using misexpressed EGFP proteins under the control of the nestin second intron enhancer. High-level EGFP expressors derived from mouse embryos included a distinct subpopulation of cells that were self-renewable and multipotent. Further, we obtained that neural progenitor cells from rat fetal spinal cords using a neurosphere technique, and demonstrated their ability to divide and differentiate into neurons in vivo, where they were integrated into the host tissue in the injured rat spinal cord with resultant behavioral improvement of the recipient rat. We also harvested tyrosine hydroxylase-positive neurons from a transgenic mouse expressing GFP under the control of the tyrosine hydroxylase promoter, and successfully transplanted them into the striatum of rats with parkinsonism with marked improvement of the neurological symptoms. Since neural stem cells can adapt well in the host CNS, studies should focus on their application as a vector in gene therapy and on the introduction in vivo or ex vivo of genes to control their proliferation and differentiation. Neural stem cells are a potential, useful source for developing new therapy for CNS disorders.


Asunto(s)
Enfermedades del Sistema Nervioso Central/terapia , Neuronas/citología , Trasplante de Células Madre , Animales , Humanos , Ratones , Enfermedad de Parkinson/terapia , Ratas , Traumatismos de la Médula Espinal/terapia
3.
Mol Cell Neurosci ; 17(2): 259-73, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11178865

RESUMEN

We generated transgenic mice carrying enhanced green fluorescent protein (EGFP) under the control of the nestin second-intronic enhancer (E/nestin:EGFP). Flow cytometry followed by in vitro assays revealed that in situ EGFP expression in the embryonic brain correlated with the mitotic index, the cogeneration of both neurons and glia, and the frequency of neurosphere formation in vitro. High-level EGFP expressors derived from embryos included a distinct subpopulation of cells that were self-renewable and multipotent, criteria that define neural stem cells (NSCs). Such cells were largely absent among lower-level or non-EGFP expressors, thereby permitting us to enrich for NSCs using EGFP expression level. In adults, although E/nestin:EGFP-positive cells included the NSC population, the frequency of neurosphere formation did not correlate directly with the level of EGFP expression. However, moderately EGFP-expressing cells in adults gained EGFP intensity when they formed neurospheres, suggesting embryonic and adult NSCs exist in different microenvironments in vivo.


Asunto(s)
Encéfalo/citología , Indicadores y Reactivos/metabolismo , Proteínas de Filamentos Intermediarios/genética , Proteínas Luminiscentes/genética , Ratones Transgénicos , Proteínas del Tejido Nervioso , Células Madre/citología , Animales , Astrocitos/citología , Astrocitos/fisiología , Encéfalo/embriología , Técnicas de Cultivo de Célula/métodos , División Celular/fisiología , Células Cultivadas , Elementos de Facilitación Genéticos/fisiología , Citometría de Flujo , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes , Proteínas de Filamentos Intermediarios/análisis , Intrones , Ratones , Mitosis/fisiología , Datos de Secuencia Molecular , Nestina , Neuronas/citología , Neuronas/fisiología , Ratas , Células Madre/fisiología , Tubulina (Proteína)/análisis
5.
Proc Natl Acad Sci U S A ; 96(17): 9885-90, 1999 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-10449789

RESUMEN

Hu proteins are mammalian embryonic lethal abnormal visual system (ELAV)-like neuronal RNA-binding proteins that contain three RNA recognition motifs. Although Drosophila ELAV is required for the correct differentiation and survival of neurons, the roles played by the Hu genes in the mammalian nervous system remain largely unknown. To explore the in vivo functions of mouse Hu proteins, we overexpressed them in rat pheochromocytoma PC12 cells, where they induced neuronal phenotype in the absence of nerve growth factor. We have characterized the functions of various forms of mHuB and mHuC bearing point mutations or deletions. Mutants of mHuC that had amino acid exchanges in the RNP1 domain of the first or second RNA recognition motifs (RRMs) lost biologic activity as well as RNA-binding activity. In addition, the mutants containing only the third RRM failed to induce the neuronal phenotype in PC12 cells and inhibited the biologic activity of cotransfected wild-type mHuB and mHuC, thus acting as a dominant-negative form. However, these mutants could not suppress the nerve growth factor-induced differentiation of PC12 cells. Further, we misexpressed wild-type and dominant-negative Hu in E9.5 mouse embryos, by using electroporation into the neural tube at the level of the rhombencephalon. mHuB and mHuC induced the ectopic expression of neuronal markers, whereas the dominant-negative forms of mHuB and mHuC suppressed the differentiation of central nervous system motor neurons. From these results, we suggest that Hu proteins are required for neuronal differentiation in the mammalian nervous system.


Asunto(s)
Antígenos de Superficie/fisiología , Sistema Nervioso Central/crecimiento & desarrollo , Proteínas del Tejido Nervioso/fisiología , Neuronas/fisiología , Sistema Nervioso Periférico/crecimiento & desarrollo , Proteínas de Unión al ARN/fisiología , Animales , Antígenos de Superficie/genética , Análisis Mutacional de ADN , Proteínas ELAV , Proteína 2 Similar a ELAV , Proteína 3 Similar a ELAV , Ratones , Proteínas del Tejido Nervioso/genética , Células PC12 , Fenotipo , Proteínas de Unión al ARN/genética , Ratas , Ribonucleoproteínas/fisiología
6.
Seishin Shinkeigaku Zasshi ; 97(9): 757-69, 1995.
Artículo en Japonés | MEDLINE | ID: mdl-8552729

RESUMEN

We report a 69-year-old woman who was clinically diagnosed as having a frontal lobe-type of Pick's disease. The initial symptoms were personality changes and problematic behaviors. The patient showed intellectual decline, "stehende Redensarten" and abnormal attitude in interpersonal situations such as inattentiveness and indifference in the course of the disease. Brain CT revealed a marked atrophy of the frontal lobes. In the terminal stage the patient had severe dementia, mutism, parkinsonism and cervical dystonia. Neuropathologically, there was a marked atrophy of the frontal lobes. The superior frontal gyrus was most severely atrophic. Histological study revealed mild to moderate loss of neurons, hyperplasia of protoplasmic astrocytes and many balooned neurons in the deep layers of the atrophied cerebral cortex. Severe neuronal loss was even seen only in a part of the superior frontal gyrus. The cerebral white manner showed marked diffuse fibrillary gliosis. There was neuronal loss with gliosis in the thalamus, lentiform nucleus, subthalamic nucleus, substantia nigra and inferior olivary nucleus. Marked gliosis was seen in the midbrain and pontine tegmentum. Sections from several levels of the spinal cord also showed marked gliosis of the gray matter. Antibodies against human tau stained massive argyrophilic thread-like structures and oligodendroglial microtubular masses in the affected lesions. Neurofibrillary tangles were localized in the hippocampus and parahippocampal region. Neither Pick's body nor senile plaque were observed. Corticobasal degeneration (CBD) is a neurodegenerative disease initially presenting with unilateral motor disturbances. Typical initial symptoms are rigidity, akinesia and apraxia of an affected arm. The clinical phenotype might depend upon the affected areas of the cerebral cortex. Our patient initially exhibited personality changes and was clinically diagnosed as having Pick's disease. Although our case had unusual distribution pattern of the cerebral atrophy, it was pathologically diagnosed as CBD. The review of the literature suggests the presence of clinical varieties in CBD.


Asunto(s)
Enfermedades de los Ganglios Basales/patología , Corteza Cerebral/patología , Demencia/patología , Anciano , Atrofia , Ganglios Basales/patología , Errores Diagnósticos , Femenino , Humanos , Degeneración Nerviosa
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