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Pike See Cheah - One of the best experts on this subject based on the ideXlab platform.
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spatiotemporal regulation of multiple overlapping sense and novel natural antisense transcripts at the nrgn and camk2n1 gene loci during mouse cerebral Corticogenesis
Cerebral Cortex, 2011Co-Authors: Seong-seng Tan, Kinghwa Ling, Chelsee A Hewitt, Tim Beissbarth, Lavinia Hyde, Pike See Cheah, Gordon K Smyth, Christopher N HahnAbstract:Nrgn and Camk2n1 are highly expressed in the brain and play an important role in synaptic long-term potentiation via regulation of Ca 21 /calmodulin-dependent protein kinase II. We have shown that the gene loci for these 2 proteins are actively transcribed in the adult cerebral cortex and feature multiple overlapping transcripts in both the sense and antisense orientations with alternative polyadenylation. These transcripts were upregulated in the adult compared with embryonic and P1.5 mouse cerebral cortices, and transcripts with different 3# untranslated region lengths showed differing expression profiles. In situ hybridization (ISH) analysis revealed spatiotemporal regulation of the Nrgn and Camk2n1 sense and natural antisense transcripts (NATs) throughout cerebral Corticogenesis. In addition, we also demonstrated that the expression of these transcripts was organ-specific. Both Nrgn and Camk2n1 sense and NATs were also upregulated in differentiating P19 teratocarcinoma cells. RNA fluorescent ISH analysis confirmed the capability of these NATs to form double-stranded RNA aggregates with the sense transcripts in the cytoplasm of cells obtained from the brain. We propose that the differential regulation of multiple sense and novel overlapping NATs at the Nrgn and Camk2n1 loci will increase the diversity of posttranscriptional regulation, resulting in cell- and time-specific regulation of their gene products during cerebral Corticogenesis and function.
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molecular networks involved in mouse cerebral Corticogenesis and spatio temporal regulation of sox4 and sox11 novel antisense transcripts revealed by transcriptome profiling
Genome Biology, 2009Co-Authors: Kinghwa Ling, Chelsee A Hewitt, Tim Beissbarth, Lavinia Hyde, Kakoli Banerjee, Pike See CheahAbstract:Development of the cerebral cortex requires highly specific spatio-temporal regulation of gene expression. It is proposed that transcriptome profiling of the cerebral cortex at various developmental time points or regions will reveal candidate genes and associated molecular pathways involved in cerebral Corticogenesis. Serial analysis of gene expression (SAGE) libraries were constructed from C57BL/6 mouse cerebral cortices of age embryonic day (E) 15.5, E17.5, postnatal day (P) 1.5 and 4 to 6 months. Hierarchical clustering analysis of 561 differentially expressed transcripts showed regionalized, stage-specific and co-regulated expression profiles. SAGE expression profiles of 70 differentially expressed transcripts were validated using quantitative RT-PCR assays. Ingenuity pathway analyses of validated differentially expressed transcripts demonstrated that these transcripts possess distinctive functional properties related to various stages of cerebral Corticogenesis and human neurological disorders. Genomic clustering analysis of the differentially expressed transcripts identified two highly transcribed genomic loci, Sox4 and Sox11, during embryonic cerebral Corticogenesis. These loci feature unusual overlapping sense and antisense transcripts with alternative polyadenylation sites and differential expression. The Sox4 and Sox11 antisense transcripts were highly expressed in the brain compared to other mouse organs and are differentially expressed in both the proliferating and differentiating neural stem/progenitor cells and P19 (embryonal carcinoma) cells. We report validated gene expression profiles that have implications for understanding the associations between differentially expressed transcripts, novel targets and related disorders pertaining to cerebral Corticogenesis. The study reports, for the first time, spatio-temporally regulated Sox4 and Sox11 antisense transcripts in the brain, neural stem/progenitor cells and P19 cells, suggesting they have an important role in cerebral Corticogenesis and neuronal/glial cell differentiation.
Emi Takahashi - One of the best experts on this subject based on the ideXlab platform.
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asymmetry of radial and symmetry of tangential neuronal migration pathways in developing human fetal brains
Frontiers in Neuroanatomy, 2016Co-Authors: Yuta Miyazaki, Jae W Song, Emi TakahashiAbstract:Abstract The radial and tangential neural migration pathways are two major neuronal migration streams in humans that are critical during Corticogenesis. Corticogenesis is a complex process of neuronal proliferation that is followed by neuronal migration and the formation of axonal connections. Existing histological assessments of these two neuronal migration pathways have limitations inherent to microscopic studies and are confined to small anatomic regions of interest. Thus, little evidence is available about their three-dimensional fiber pathways and development throughout the entire brain. In this study, we imaged and analyzed radial and tangential migration pathways in the whole human brain using high-angular resolution diffusion MR imaging (HARDI) tractography. We imaged ten fixed, postmortem fetal (17 gestational weeks (GW), 18 GW, 19 GW, three 20 GW, three 21 GW and 22 GW) and eight in vivo newborn (two 30 GW, 34 GW, 35 GW and four 40 GW) brains with no neurological/pathological conditions. We statistically compared the volume of the left and right radial and tangential migration pathways, and the volume of the radial migration pathways of the anterior and posterior regions of the brain. In specimens 22 GW or younger, the volume of radial migration pathways of the left hemisphere was significantly larger than that of the right hemisphere. The volume of posterior radial migration pathways was also larger when compared to the anterior pathways in specimens 22 GW or younger. In contrast, no significant differences were observed in the radial migration pathways of brains older than 22 GW. Moreover, our study did not identify any significant differences in volumetric laterality in the tangential migration pathways. These results suggest that these two neuronal migration pathways develop and regress differently, and radial neuronal migration varies regionally based on hemispheric and anterior-posterior laterality, potentially explaining regional differences in the amount of excitatory neurons that migrate along the radial scaffold.
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asymmetry of radial and symmetry of tangential neuronal migration pathways in developing human fetal brains
Frontiers in Neuroanatomy, 2016Co-Authors: Yuta Miyazaki, Jae W Song, Emi TakahashiAbstract:Abstract The radial and tangential neural migration pathways are two major neuronal migration streams in humans that are critical during Corticogenesis. Corticogenesis is a complex process of neuronal proliferation that is followed by neuronal migration and the formation of axonal connections. Existing histological assessments of these two neuronal migration pathways have limitations inherent to microscopic studies and are confined to small anatomic regions of interest. Thus, little evidence is available about their three-dimensional fiber pathways and development throughout the entire brain. In this study, we imaged and analyzed radial and tangential migration pathways in the whole human brain using high-angular resolution diffusion MR imaging (HARDI) tractography. We imaged ten fixed, postmortem fetal (17 gestational weeks (GW), 18 GW, 19 GW, three 20 GW, three 21 GW and 22 GW) and eight in vivo newborn (two 30 GW, 34 GW, 35 GW and four 40 GW) brains with no neurological/pathological conditions. We statistically compared the volume of the left and right radial and tangential migration pathways, and the volume of the radial migration pathways of the anterior and posterior regions of the brain. In specimens 22 GW or younger, the volume of radial migration pathways of the left hemisphere was significantly larger than that of the right hemisphere. The volume of posterior radial migration pathways was also larger when compared to the anterior pathways in specimens 22 GW or younger. In contrast, no significant differences were observed in the radial migration pathways of brains older than 22 GW. Moreover, our study did not identify any significant differences in volumetric laterality in the tangential migration pathways. These results suggest that these two neuronal migration pathways develop and regress differently, and radial neuronal migration varies regionally based on hemispheric and anterior-posterior laterality, potentially explaining regional differences in the amount of excitatory neurons that migrate along the radial scaffold.
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radial and tangential neuronal migration pathways in the human fetal brain anatomically distinct patterns of diffusion mri coherence
NeuroImage, 2013Co-Authors: James Kolasinski, Emi Takahashi, Allison Stevens, Thomas Benner, Bruce Fischl, Lilla Zollei, Ellen P GrantAbstract:Corticogenesis is underpinned by a complex process of subcortical neuroproliferation, followed by highly orchestrated cellular migration. A greater appreciation of the processes involved in human fetal Corticogenesis is vital to gaining an understanding of how developmental disturbances originating in gestation could establish a variety of complex neuropathology manifesting in childhood, or even in adult life. Magnetic resonance imaging modalities offer a unique insight into anatomical structure, and increasingly infer information regarding underlying microstructure in the human brain. In this study we applied a combination of high-resolution structural and diffusion-weighted magnetic resonance imaging to a unique cohort of three post-mortem fetal brain specimens, aged between 19 and 22 post-conceptual weeks. Specifically, we sought to assess patterns of diffusion coherence associated with subcortical neuroproliferative structures: the pallial ventricular/subventricular zone and subpallial ganglionic eminence. Two distinct three-dimensional patterns of diffusion coherence were evident: a clear radial pattern originating in ventricular/subventricular zone, and a tangentio-radial patterns originating in ganglionic eminence. These patterns appeared to regress in a caudo-rostral and lateral-ventral to medial-dorsal direction across the short period of fetal development under study. Our findings demonstrate for the first time distinct patterns of diffusion coherence associated with known anatomical proliferative structures. The radial pattern associated with dorsopallial ventricular/subventricular zone and the tangentio-radial pattern associated with subpallial ganglionic eminence are consistent with reports of radial–glial mediated neuronal migration pathways identified during human Corticogenesis, supported by our prior studies of comparative fetal diffusion MRI and histology. The ability to assess such pathways in the fetal brain using MR imaging offers a unique insight into three-dimensional trajectories beyond those visualized using traditional histological techniques. Our results suggest that ex-vivo fetal MRI is a potentially useful modality in understanding normal human development and various disease processes whose etiology may originate in aberrant fetal neuronal migration.
Colette Dehay - One of the best experts on this subject based on the ideXlab platform.
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Table1.PDF
2018Co-Authors: Ugo Borello, Barbara Berarducci, Edwige Delahaye, David J. Price, Colette DehayAbstract:Multiple signals control the balance between proliferation and differentiation of neural progenitor cells during Corticogenesis. A key point of this regulation is the control of G1 phase length, which is regulated by the Cyclin/Cdks complexes. Using genome-wide chromatin immunoprecipitation assay and mouse genetics, we have explored the transcriptional regulation of Cyclin D1 (Ccnd1) during the early developmental stages of the mouse cerebral cortex. We found evidence that SP8 binds to the Ccnd1 locus on exon regions. In vitro experiments show SP8 binding activity on Ccnd1 gene 3′-end, and point to a putative role for SP8 in modulating PAX6-mediated repression of Ccnd1 along the dorso-ventral axis of the developing pallium, creating a medialLow-lateralHigh gradient of neuronal differentiation. Activation of Ccnd1 through the promoter/5′-end of the gene does not depend on SP8, but on βcatenin (CTNNB1). Importantly, alteration of the Sp8 level of expression in vivo affects Ccnd1 expression during early Corticogenesis. Our results indicate that Ccnd1 regulation is the result of multiple signals and that SP8 is a player in this regulation, revealing an unexpected and potentially novel mechanism of transcriptional activation.
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SP8 Transcriptional Regulation of Cyclin D1 During Mouse Early Corticogenesis
Frontiers Media S.A., 2018Co-Authors: Barbara Berarducci, Ugo Borello, Edwige Delahaye, David J. Price, Colette DehayAbstract:Multiple signals control the balance between proliferation and differentiation of neural progenitor cells during Corticogenesis. A key point of this regulation is the control of G1 phase length, which is regulated by the Cyclin/Cdks complexes. Using genome-wide chromatin immunoprecipitation assay and mouse genetics, we have explored the transcriptional regulation of Cyclin D1 (Ccnd1) during the early developmental stages of the mouse cerebral cortex. We found evidence that SP8 binds to the Ccnd1 locus on exon regions. In vitro experiments show SP8 binding activity on Ccnd1 gene 3′-end, and point to a putative role for SP8 in modulating PAX6-mediated repression of Ccnd1 along the dorso-ventral axis of the developing pallium, creating a medialLow-lateralHigh gradient of neuronal differentiation. Activation of Ccnd1 through the promoter/5′-end of the gene does not depend on SP8, but on βcatenin (CTNNB1). Importantly, alteration of the Sp8 level of expression in vivo affects Ccnd1 expression during early Corticogenesis. Our results indicate that Ccnd1 regulation is the result of multiple signals and that SP8 is a player in this regulation, revealing an unexpected and potentially novel mechanism of transcriptional activation
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mitotic spindle asymmetry a wnt pcp regulated mechanism generating asymmetrical division in cortical precursors
Cell Reports, 2014Co-Authors: Véronique Cortay, Dorothée Patti, Delphine Delaunay, Kenneth Knoblauch, Colette DehayAbstract:The regulation of asymmetric cell division (ACD) during Corticogenesis is incompletely understood. We document that spindle-size asymmetry (SSA) between the two poles occurs during Corticogenesis and parallels ACD. SSA appears at metaphase and is maintained throughout division, and we show it is necessary for proper neurogenesis. Imaging of spindle behavior and division outcome reveals that neurons preferentially arise from the larger-spindle pole. Mechanistically, SSA magnitude is controlled by Wnt7a and Vangl2, both members of the Wnt/planar cell polarity (PCP)-signaling pathway, and relayed to the cell cortex by P-ERM proteins. In vivo, Vangl2 and P-ERM downregulation promotes early cell-cycle exit and prevents the proper generation of late-born neurons. Thus, SSA is a core component of ACD that is conserved in invertebrates and vertebrates and plays a key role in the tight spatiotemporal control of self-renewal and differentiation during mammalian Corticogenesis.
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the concerted modulation of proliferation and migration contributes to the specification of the cytoarchitecture and dimensions of cortical areas
Cerebral Cortex, 2006Co-Authors: Agnes Lukaszewicz, Henry Kennedy, Véronique Cortay, Pascale Giroud, Michel Berland, Iain Smart, Colette DehayAbstract:Regionalization of cell-cycle kinetics of cortical precursors has been described in non-human primates and rodents indicating a fate map of areal distinct proliferative programs in the germinal zones of the neocortex. It remains to be understood how proliferative gradients during Corticogenesis are transcribed into a stepwise function to form adult areal borders. Here we have used the monkey areas17 and 18, which show striking cytoarchitectonic differences as a model system for studying how developmental events establish areal boundaries in the adult. We present data indicating that the events that are involved in the formation of a sharp border separating two areas involve an orchestration of diverse phenomena including differential rates of proliferation, migration and tangential expansion.
David Price - One of the best experts on this subject based on the ideXlab platform.
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the generation of superficial cortical layers is regulated by levels of the transcription factor pax6
Cerebral Cortex, 2011Co-Authors: Petrina A Georgala, Martine Manuel, David PriceAbstract:The ventricular zone (VZ) of the embryonic dorsal telencephalon is a major site for generating cortical projection neurons. The transcription factor Pax6 is highly expressed in apical progenitors (APs) residing in the VZ from the earliest stages of Corticogenesis. Previous studies mainly focused on Pax6(-/-) mice have implicated Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of superficial cortical layers. We analyzed the developing cortex of PAX77 transgenic mice that overexpress Pax6 in its normal domains of expression. We show that Pax6 overexpression increases cell cycle length of APs and drives the system toward neurogenesis. These effects are specific to late stages of Corticogenesis, when superficial layer neurons are normally generated, in cortical regions that express Pax6 at the highest levels. The number of superficial layer neurons is reduced in postnatal PAX77 mice, whereas radial migration and lamina specification of cortical neurons are not affected by Pax6 overexpression. Conditional deletion of Pax6 in cortical progenitors at midstages of Corticogenesis, by using a tamoxifen-inducible Emx1-CreER line, affected both numbers and specification of late-born neurons in superficial layers of the mutant cortex. Our analyses suggest that correct levels of Pax6 are essential for normal production of superficial layers of the cortex.
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pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors
Development, 2002Co-Authors: Guillermo Estivilltorrus, David Price, Helen Pearson, Veronica Van Heyningen, P RashbassAbstract:In the proliferative zone of the developing cerebral cortex, multipotential progenitors predominate early in development and divide to increase the progenitor pool. As Corticogenesis progresses, proportionately fewer progenitors are produced and, instead, cell divisions yield higher numbers of postmitotic neurones or glial cells. As the switch from the generation of progenitors to that of differentiated cells occurs, the orientation of cell division alters from predominantly symmetrical to predominantly asymmetrical. It has been hypothesised that symmetrical divisions expand the progenitor pool, whereas asymmetrical divisions generate postmitotic cells, although this remains to be proved. The molecular mechanisms regulating these processes are poorly understood. The transcription factor Pax6 is highly expressed in the cortical proliferative zone and there are morphological defects in the Pax6(Sey/Sey) (Pax6 null) cortex, but little is known about the principal cellular functions of Pax6 in this region. We have analysed the cell-cycle kinetics, the progenitor cleavage orientation and the onset of expression of differentiation markers in Pax6(Sey/Sey) cortical cells in vivo and in vitro. We showed that, early in Corticogenesis at embryonic day (E) 12.5, the absence of Pax6 accelerated cortical development in vivo, shortening the cell cycle and the time taken for the onset of expression of neural-specific markers. This also occurred in dissociated culture of isolated cortical cells, indicating that the changes were intrinsic to the cortical cells. From E12.5 to E15.5, proportions of asymmetrical divisions increased more rapidly in mutant than in wild-type embryos. By E15.5, interkinetic nuclear migration during the cell cycle was disrupted and the length of the cell cycle was significantly longer than normal in the Pax6(Sey/Sey) cortex, with a lengthening of S phase. Together, these results show that Pax6 is required in developing cortical progenitors to control the cell-cycle duration, the rate of progression from symmetrical to asymmetrical division and the onset of expression of neural-specific markers.
Kinghwa Ling - One of the best experts on this subject based on the ideXlab platform.
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spatiotemporal regulation of multiple overlapping sense and novel natural antisense transcripts at the nrgn and camk2n1 gene loci during mouse cerebral Corticogenesis
Cerebral Cortex, 2011Co-Authors: Seong-seng Tan, Kinghwa Ling, Chelsee A Hewitt, Tim Beissbarth, Lavinia Hyde, Pike See Cheah, Gordon K Smyth, Christopher N HahnAbstract:Nrgn and Camk2n1 are highly expressed in the brain and play an important role in synaptic long-term potentiation via regulation of Ca 21 /calmodulin-dependent protein kinase II. We have shown that the gene loci for these 2 proteins are actively transcribed in the adult cerebral cortex and feature multiple overlapping transcripts in both the sense and antisense orientations with alternative polyadenylation. These transcripts were upregulated in the adult compared with embryonic and P1.5 mouse cerebral cortices, and transcripts with different 3# untranslated region lengths showed differing expression profiles. In situ hybridization (ISH) analysis revealed spatiotemporal regulation of the Nrgn and Camk2n1 sense and natural antisense transcripts (NATs) throughout cerebral Corticogenesis. In addition, we also demonstrated that the expression of these transcripts was organ-specific. Both Nrgn and Camk2n1 sense and NATs were also upregulated in differentiating P19 teratocarcinoma cells. RNA fluorescent ISH analysis confirmed the capability of these NATs to form double-stranded RNA aggregates with the sense transcripts in the cytoplasm of cells obtained from the brain. We propose that the differential regulation of multiple sense and novel overlapping NATs at the Nrgn and Camk2n1 loci will increase the diversity of posttranscriptional regulation, resulting in cell- and time-specific regulation of their gene products during cerebral Corticogenesis and function.
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molecular networks involved in mouse cerebral Corticogenesis and spatio temporal regulation of sox4 and sox11 novel antisense transcripts revealed by transcriptome profiling
Genome Biology, 2009Co-Authors: Kinghwa Ling, Chelsee A Hewitt, Tim Beissbarth, Lavinia Hyde, Kakoli Banerjee, Pike See CheahAbstract:Development of the cerebral cortex requires highly specific spatio-temporal regulation of gene expression. It is proposed that transcriptome profiling of the cerebral cortex at various developmental time points or regions will reveal candidate genes and associated molecular pathways involved in cerebral Corticogenesis. Serial analysis of gene expression (SAGE) libraries were constructed from C57BL/6 mouse cerebral cortices of age embryonic day (E) 15.5, E17.5, postnatal day (P) 1.5 and 4 to 6 months. Hierarchical clustering analysis of 561 differentially expressed transcripts showed regionalized, stage-specific and co-regulated expression profiles. SAGE expression profiles of 70 differentially expressed transcripts were validated using quantitative RT-PCR assays. Ingenuity pathway analyses of validated differentially expressed transcripts demonstrated that these transcripts possess distinctive functional properties related to various stages of cerebral Corticogenesis and human neurological disorders. Genomic clustering analysis of the differentially expressed transcripts identified two highly transcribed genomic loci, Sox4 and Sox11, during embryonic cerebral Corticogenesis. These loci feature unusual overlapping sense and antisense transcripts with alternative polyadenylation sites and differential expression. The Sox4 and Sox11 antisense transcripts were highly expressed in the brain compared to other mouse organs and are differentially expressed in both the proliferating and differentiating neural stem/progenitor cells and P19 (embryonal carcinoma) cells. We report validated gene expression profiles that have implications for understanding the associations between differentially expressed transcripts, novel targets and related disorders pertaining to cerebral Corticogenesis. The study reports, for the first time, spatio-temporally regulated Sox4 and Sox11 antisense transcripts in the brain, neural stem/progenitor cells and P19 cells, suggesting they have an important role in cerebral Corticogenesis and neuronal/glial cell differentiation.
