The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Vinodh Narayanan - One of the best experts on this subject based on the ideXlab platform.
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abnormalities of cell packing density and dendritic complexity in the mecp2 a140v mouse model of rett syndrome x linked mental retardation
BMC Neuroscience, 2010Co-Authors: Garilyn Jentarra, Shannon Olfers, Stephen G Rice, Nishit Srivastava, Gregg E Homanics, Mary E Blue, S Naidu, Vinodh NarayananAbstract:Rett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X-linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl-CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX. We report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis. We have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms.
Guiquan Chen - One of the best experts on this subject based on the ideXlab platform.
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Loss of FMRP Impaired Hippocampal Long-Term Plasticity and Spatial Learning in Rats
Frontiers in molecular neuroscience, 2017Co-Authors: Yonglu Tian, Chaojuan Yang, Shujiang Shang, Yijun Cai, Xiaofei Deng, Jian Zhang, Feng Shao, Desheng Zhu, Yunbo Liu, Guiquan ChenAbstract:Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene that inactivate expression of the gene product, the fragile X mental retardation 1 protein (FMRP). In this study, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology to generate Fmr1 knockout (KO) rats by disruption of the fourth exon of the Fmr1 gene. Western blotting analysis confirmed that the FMRP was absent from the brains of the Fmr1 KO rats (Fmr1exon4-KO). Electrophysiological analysis revealed that the theta-burst stimulation (TBS)–induced long-term potentiation (LTP) and the low-frequency stimulus (LFS)–induced long-term depression (LTD)were decreased in the hippocampal Schaffer collateral pathway of the Fmr1exon4-KO rats. Short-term plasticity, measured as the paired-pulse ratio, remained normal in the KO rats. The synaptic strength mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was also impaired. Consistent with previous reports, the Fmr1exon4-KO rats demonstrated an enhanced 3,5-dihydroxyphenylglycine (DHPG)–induced LTD in the present study, and this enhancement is insensitive to protein translation. In addition, the Fmr1exon4-KO rats showed deficits in the probe trial in the Morris water maze test. These results demonstrate that deletion of the Fmr1 gene in rats specifically impairs long-term synaptic plasticity and hippocampus-dependent learning in a manner resembling the key symptoms of FXS. Furthermore, the Fmr1exon4-KO rats displayed impaired social interaction and Macroorchidism, the results consistent with those observed in patients with FXS. Thus, Fmr1exon4-KO rats constitute a novel rat model of FXS that complements existing mouse models.
Chen Guiquan - One of the best experts on this subject based on the ideXlab platform.
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Loss of FMRP Impaired Hippocampal Long-Term Plasticity and Spatial Learning in Rats
FRONTIERS IN MOLECULAR NEUROSCIENCE, 2017Co-Authors: Tian Yonglu, Yang Chaojuan, Shang Shujiang, Cai Yijun, Deng Xiaofei, Zhang Jian, Shao Feng, Zhu Desheng, Liu Yunbo, Chen GuiquanAbstract:Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene that inactivate expression of the gene product, the fragile X mental retardation 1 protein (FMRP). In this study, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology to generate Fmr1 knockout (KO) rats by disruption of the fourth exon of the Fmr1 gene. Western blotting analysis confirmed that the FMRP was absent from the brains of the Fmr1 KO rats (Fmr1(exon4-KO)). Electrophysiological analysis revealed that the theta-burst stimulation (TBS)-induced long-term potentiation (LTP) and the low-frequency stimulus (LFS)-induced long-term depression (LTD) were decreased in the hippocampal Schaffer collateral pathway of the Fmr1(exon4-KO) rats. Short-term plasticity, measured as the paired-pulse ratio, remained normal in the KO rats. The synaptic strength mediated by the a -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was also impaired. Consistent with previous reports, the Fmr1(exon4-KO) rats demonstrated an enhanced 3,5-dihydroxyphenylglycine (DHPG)-induced LTD in the present study, and this enhancement is insensitive to protein translation. In addition, the Fmr1(exon4-KO) rats showed deficits in the probe trial in the Morris water maze test. These results demonstrate that deletion of the Fmr1 gene in rats specifically impairs long-term synaptic plasticity and hippocampus-dependent learning in a manner resembling the key symptoms of FXS. Furthermore, the Fmr1(exon4-KO) rats displayed impaired social interaction and Macroorchidism, the results consistent with those observed in patients with FXS. Thus, Fmr1exon4 KO rats constitute a novel rat model of FXS that complements existing mouse models.National Key Research and Development Program of China [2017YFA0105201, 2012YQ03026004, 2014CB942804]; National Science Foundation of China [31670842]; Beijing Municipal Science and Technology Commission [Z161100002616021, Z161100000216154]; Seeding Grant for Medicine and Life Sciences of Peking University [2014-MB-11]SCI(E)ARTICLE1
Ben A Oostra - One of the best experts on this subject based on the ideXlab platform.
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Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development
1998Co-Authors: Karin E. Slegtenhorst-eegdeman, Cathy E Bakker, Ben A Oostra, Dirk G. De Rooij, Miriam Verhoef-post, Anton J. Grootegoed, Axel P. N. ThemmenAbstract:The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 59-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, Macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of Macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate o
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Macroorchidism in fmr1 knockout mice is caused by increased sertoli cell proliferation during testicular development
Endocrinology, 1998Co-Authors: Karin E Slegtenhorsteegdeman, Cathy E Bakker, Ben A Oostra, Dirk G. De Rooij, Anton J. Grootegoed, Miriam Verhoefpost, Henk J G Van De Kant, Axel P. N. ThemmenAbstract:The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5'-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, Macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of Macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate of Sertoli cell proliferation is increased from embryonic day 12 to 15 days postnatally. The onset and length of the period of Sertoli cell proliferation were not changed compared with those in the control males. Serum levels of FSH, FSH receptor messenger RNA expression, and short term effects of FSH on Sertoli cell function, as measured by down-regulation of FSH receptor messenger RNA, were not changed. We conclude that Macroorchidism in Fmr1 knockout male mice is caused by an increased rate of Sertoli cell proliferation. This increase does not appear to be the result of a major change in FSH signal transduction in Fmr1 knockout mice.
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Differential Expression of FMR1, FXR1 and FXR2 Proteins in Human Brain and Testis
Human Molecular Genetics, 1997Co-Authors: Filippo Tamanini, Rob Willemsen, Ben A Oostra, Leontine Van Unen, Carola Bontekoe, Hans Galjaard, A T HoogeveenAbstract:textabstractLack of expression of the fragile X mental retardation protein (FMRP) results in mental retardation and Macroorchidism, seen as the major pathological symptoms in fragile X patients. FMRP is a cytoplasmic RNA-binding protein which cosediments with the 60S ribosomal subunit. Recently, two proteins homologous to FMRP were discovered: FXR1 and FXR2. These novel proteins interact with FMRP and with each other and they are also associated with the 60S ribosomal subunit. Here, we studied the expression pattern of the three proteins in brain and testis by immunohistochemistry. In adult brain, FMR1, FXR1 and FXR2 proteins are coexpressed in the cytoplasm of specific differentiated neurons only. However, we observed a different expression pattern in fetal brain as well as in adult and fetal testis, suggesting independent functions for the three proteins in those tissues during embryonic development and adult life.
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Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis
1997Co-Authors: Rob Willemsen, Ben A Oostra, Leontine Van Unen, Carola Bontekoe, Hans Galjaard, A T HoogeveenAbstract:Lack of expression of the fragile X mental retardation protein (FMRP) results in mental retardation and Macroorchidism, seen as the major pathological symptoms in fragile X patients. FMRP is a cytoplasmic RNA-binding protein which cosediments with the 60S ribosomal subunit. Recently, two proteins homologous to FMRP were discovered: FXR1 and FXR2. These novel proteins interact with FMRP and with each other and they are also associated with the 60S ribosomal subunit. Here, we studied the expression pattern of the three proteins in brain and testis by immuno-histochemistry. In adult brain, FMR1, FXR1 and FXR2 proteins are coexpressed in the cytoplasm of specific differentiated neurons only. However, we observed a different expression pattern in fetal brain as well as in adult and fetal testis, suggesting independent functions for the three proteins in those tissues during embryonic development and adult life
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fmr1 knockout mice a model to study fragile x mental retardation
Cell, 1994Co-Authors: Cathy E Bakker, C Verheij, Rob Willemsen, Robert Van Der Helm, Frank Oerlemans, M Vermey, Anne E Bygrave, A T Hoogeveen, Ben A Oostra, Edwin ReyniersAbstract:Abstract Male patients with fragile X syndrome lack FMR1 protein due to silencing of the FMR1 gene by amplification of a CGG repeat and subsequent methylation of the promoter region. The absence of FMR1 protein leads to mental retardation, aberrant behavior, and Macroorchidism. Hardly anything is known about the physiological function of FMR1 and the pathological mechanisms leading to these symptoms. Therefore, we designed a knockout model for the fragile X syndrome in mice. The knockout mice lack normal Fmr1 protein and show Macroorchidism, learning deficits, and hyperactivity. Consequently, this knockout mouse may serve as a valuable tool in the elucidation of the physiological role of FMR1 and the mechanisms involved in Macroorchidism, abnormal behavior, and mental retardation.
Cathy E Bakker - One of the best experts on this subject based on the ideXlab platform.
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Macroorchidism in fmr1 knockout mice is caused by increased sertoli cell proliferation during testicular development
Endocrinology, 1998Co-Authors: Karin E Slegtenhorsteegdeman, Cathy E Bakker, Ben A Oostra, Dirk G. De Rooij, Anton J. Grootegoed, Miriam Verhoefpost, Henk J G Van De Kant, Axel P. N. ThemmenAbstract:The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5'-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, Macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of Macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate of Sertoli cell proliferation is increased from embryonic day 12 to 15 days postnatally. The onset and length of the period of Sertoli cell proliferation were not changed compared with those in the control males. Serum levels of FSH, FSH receptor messenger RNA expression, and short term effects of FSH on Sertoli cell function, as measured by down-regulation of FSH receptor messenger RNA, were not changed. We conclude that Macroorchidism in Fmr1 knockout male mice is caused by an increased rate of Sertoli cell proliferation. This increase does not appear to be the result of a major change in FSH signal transduction in Fmr1 knockout mice.
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Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development
1998Co-Authors: Karin E. Slegtenhorst-eegdeman, Cathy E Bakker, Ben A Oostra, Dirk G. De Rooij, Miriam Verhoef-post, Anton J. Grootegoed, Axel P. N. ThemmenAbstract:The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 59-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, Macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of Macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate o
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fmr1 knockout mice a model to study fragile x mental retardation
Cell, 1994Co-Authors: Cathy E Bakker, C Verheij, Rob Willemsen, Robert Van Der Helm, Frank Oerlemans, M Vermey, Anne E Bygrave, A T Hoogeveen, Ben A Oostra, Edwin ReyniersAbstract:Abstract Male patients with fragile X syndrome lack FMR1 protein due to silencing of the FMR1 gene by amplification of a CGG repeat and subsequent methylation of the promoter region. The absence of FMR1 protein leads to mental retardation, aberrant behavior, and Macroorchidism. Hardly anything is known about the physiological function of FMR1 and the pathological mechanisms leading to these symptoms. Therefore, we designed a knockout model for the fragile X syndrome in mice. The knockout mice lack normal Fmr1 protein and show Macroorchidism, learning deficits, and hyperactivity. Consequently, this knockout mouse may serve as a valuable tool in the elucidation of the physiological role of FMR1 and the mechanisms involved in Macroorchidism, abnormal behavior, and mental retardation.
