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The neocortex of the adult brain consists of neurons and glia that are generated by precursor cells of the embryonic ventricular zone. In general, glia are generated after neurons during development, but radial glia are an exception to... more
The neocortex of the adult brain consists of neurons and glia that are generated by precursor cells of the embryonic ventricular zone. In general, glia are generated after neurons during development, but radial glia are an exception to this rule. Radial glia are generated before neurogenesis and guide neuronal migration. Radial glia are mitotically active throughout neurogenesis, and disappear or
Research Interests: Pharmacology, Biochemistry, Bioinformatics, Evolutionary Biology, Genetics, and 51 moreMarine Biology, Neuroscience, Environmental Science, Geophysics, Physics, Materials Science, Quantum Physics, Developmental Biology, Immunology, Climate Change, Molecular Biology, Structural Biology, Genomics, RNA, Computational Biology, Transcriptomics, Biotechnology, Systems Biology, Cancer, Biology, Metabolomics, Cell Cycle, Proteomics, Ecology, Drug Discovery, Evolution, Nanotechnology, Astrophysics, Neurobiology, Medicine, Multidisciplinary, Palaeobiology, Functional Genomics, Nature, Signal Transduction, Astronomy, DNA, Mitosis, Cell Differentiation, Video microscopy, Animals, Cell Signalling, Medical Research, Astrocyte, Glial Cell, Neurons, Rats, Radial Glia, Neocortex, Neuronal Migration, and Earth Science(Marine Biology, Neuroscience, Environmental Science, Geophysics, Physics, Materials Science, Quantum Physics, Developmental Biology, Immunology, Climate Change, Molecular Biology, Structural Biology, Genomics, RNA, Computational Biology, Transcriptomics, Biotechnology, Systems Biology, Cancer, Biology, Metabolomics, Cell Cycle, Proteomics, Ecology, Drug Discovery, Evolution, Nanotechnology, Astrophysics, Neurobiology, Medicine, Multidisciplinary, Palaeobiology, Functional Genomics, Nature, Signal Transduction, Astronomy, DNA, Mitosis, Cell Differentiation, Video microscopy, Animals, Cell Signalling, Medical Research, Astrocyte, Glial Cell, Neurons, Rats, Radial Glia, Neocortex, Neuronal Migration, and Earth Science)
(Marine Biology, Neuroscience, Environmental Science, Geophysics, Physics, Materials Science, Quantum Physics, Developmental Biology, Immunology, Climate Change, Molecular Biology, Structural Biology, Genomics, RNA, Computational Biology, Transcriptomics, Biotechnology, Systems Biology, Cancer, Biology, Metabolomics, Cell Cycle, Proteomics, Ecology, Drug Discovery, Evolution, Nanotechnology, Astrophysics, Neurobiology, Medicine, Multidisciplinary, Palaeobiology, Functional Genomics, Nature, Signal Transduction, Astronomy, DNA, Mitosis, Cell Differentiation, Video microscopy, Animals, Cell Signalling, Medical Research, Astrocyte, Glial Cell, Neurons, Rats, Radial Glia, Neocortex, Neuronal Migration, and Earth Science)
NMDA receptors play important roles in learning and memory and in sculpting neural connections during development. After the period of peak cortical plasticity, NMDA receptor-mediated EPSCs (NMDAR EPSCs) decrease in duration. A likely... more
NMDA receptors play important roles in learning and memory and in sculpting neural connections during development. After the period of peak cortical plasticity, NMDA receptor-mediated EPSCs (NMDAR EPSCs) decrease in duration. A likely mechanism for this change in NMDA receptor properties is the molecular alteration of NMDA receptor structure by regulation of NMDA receptor subunit gene expression. The four modulatory NMDAR2A-D (NR2A-D) NMDA receptor subunits are known to alter NMDA receptor properties, and the expression of these subunits is regulated developmentally. It is unclear, however, how the four NR2 subunits are expressed in individual neurons and which NR2 subunits are important to the regulation of NMDA receptor properties during development in vivo. Analysis of NR2 subunit gene expression in single characterized neurons of postnatal neocortex revealed that cells expressing NR2A subunit mRNA had faster NMDAR EPSCs than cells not expressing this subunit, regardless of postn...
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Cells within the ventricular zone (VZ) of developing neocortex are coupled together into clusters by gap junction channels. The specific role of clustering in cortical neurogenesis is unknown; however, clustering provides a means for... more
Cells within the ventricular zone (VZ) of developing neocortex are coupled together into clusters by gap junction channels. The specific role of clustering in cortical neurogenesis is unknown; however, clustering provides a means for spatially restricted local interactions ...
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We have made patch-clamp recordings from slices of fetal and postnatal rat neocortex in order to study the initial expression and activation of NMDA channels. Recordings from both whole cells and outside-out patches indicated that... more
We have made patch-clamp recordings from slices of fetal and postnatal rat neocortex in order to study the initial expression and activation of NMDA channels. Recordings from both whole cells and outside-out patches indicated that functional NMDA channels are expressed on neurons within the cortical plate, but not on younger cells within the ventricular zone. The NMDA channels on cortical plate neurons had a unitary conductance of approximately 40 pS, had a mean open time of approximately 6 msec, required glycine to open, and were blocked in a voltage-dependent manner by magnesium. These precocious channels were present before the appearance of functional synaptic activity, yet like NMDA channels in the mature neocortex, they were spontaneously activated by an agonist within brain slices. These results demonstrate that NMDA channels are initially expressed on neocortical neurons some time between the last mitotic division within the ventricular zone and completion of migration into ...
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Recent work suggests that radial glial cells represent many, if not most, of the neuronal progenitors in the developing cortex. Asymmetric cell division of radial glia results in the self-renewal of the radial glial cell and the birth of... more
Recent work suggests that radial glial cells represent many, if not most, of the neuronal progenitors in the developing cortex. Asymmetric cell division of radial glia results in the self-renewal of the radial glial cell and the birth of a neuron. Among the proteins that direct cell fate in Drosophila melanogaster that have known mammalian homologs, Numb is the best
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The embryonic ventricular zone (VZ) of the cerebral cortex contains migrating neurons, radial glial cells, and a large pop- ulation of cycling progenitor cells that generate newborn neu- rons. The latter two cell classes have been assumed... more
The embryonic ventricular zone (VZ) of the cerebral cortex contains migrating neurons, radial glial cells, and a large pop- ulation of cycling progenitor cells that generate newborn neu- rons. The latter two cell classes have been assumed for some time to be distinct in both function and anatomy, but the cellular anatomy of the progenitor cell type has remained poorly
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Non-neurogenic cell types, such as cortical astroglia and fibroblasts, can be directly converted into neurons by the overexpression of defined transcription factors. Normally, the cellular phenotype of such differentiated cells is... more
Non-neurogenic cell types, such as cortical astroglia and fibroblasts, can be directly converted into neurons by the overexpression of defined transcription factors. Normally, the cellular phenotype of such differentiated cells is remarkably stable and resists direct cell transdifferentiation. Here we show that the Ink4a/Arf (also known as Cdkn2a) locus is a developmental barrier to direct neuronal transdifferentiation induced by transcription factor overexpression. With serial passage in vitro, wild-type postnatal cortical astroglia become progressively resistant to Dlx2-induced neuronal transdifferentiation. In contrast, the neurogenic competence of Ink4a/Arf-deficient astroglia is both greatly increased and does not diminish through serial cell culture passage. Electrophysiological analysis further demonstrates the neuronal identity of cells induced from Ink4a/Arf-null astroglia, and short hairpin RNA-mediated acute knockdown of p16Ink4a and p19Arf p16(Ink4a) and p19(Arf) indicat...
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The neocortex of the adult brain consists of neurons and glia that are generated by precursor cells of the embryonic ventricular zone. In general, glia are generated after neurons during development, but radial glia are an exception to... more
The neocortex of the adult brain consists of neurons and glia that are generated by precursor cells of the embryonic ventricular zone. In general, glia are generated after neurons during development, but radial glia are an exception to this rule. Radial glia are generated before neurogenesis and guide neuronal migration. Radial glia are mitotically active throughout neurogenesis, and disappear or become astrocytes when neuronal migration is complete. Although the lineage relationships of cortical neurons and glia have been explored, the clonal relationship of radial glia to other cortical cells remains unknown. It has been suggested that radial glia may be neuronal precursors, but this has not been demonstrated in vivo. We have used a retroviral vector encoding enhanced green fluorescent protein to label precursor cells in vivo and have examined clones 1-3 days later using morphological, immunohistochemical and electrophysiological techniques. Here we show that clones consist of mitotic radial glia and postmitotic neurons, and that neurons migrate along clonally related radial glia. Time-lapse images show that proliferative radial glia generate neurons. Our results support the concept that a lineage relationship between neurons and proliferative radial glia may underlie the radial organization of neocortex.
Research Interests: Pharmacology, Biochemistry, Bioinformatics, Evolutionary Biology, Genetics, and 51 moreMarine Biology, Neuroscience, Environmental Science, Geophysics, Physics, Materials Science, Quantum Physics, Developmental Biology, Immunology, Climate Change, Molecular Biology, Structural Biology, Genomics, RNA, Computational Biology, Transcriptomics, Biotechnology, Systems Biology, Cancer, Biology, Metabolomics, Cell Cycle, Proteomics, Ecology, Drug Discovery, Evolution, Nanotechnology, Astrophysics, Neurobiology, Medicine, Multidisciplinary, Palaeobiology, Functional Genomics, Nature, Signal Transduction, Astronomy, DNA, Mitosis, Cell Differentiation, Video microscopy, Animals, Cell Signalling, Medical Research, Astrocyte, Glial Cell, Neurons, Rats, Radial Glia, Neocortex, Neuronal Migration, and Earth Science(Marine Biology, Neuroscience, Environmental Science, Geophysics, Physics, Materials Science, Quantum Physics, Developmental Biology, Immunology, Climate Change, Molecular Biology, Structural Biology, Genomics, RNA, Computational Biology, Transcriptomics, Biotechnology, Systems Biology, Cancer, Biology, Metabolomics, Cell Cycle, Proteomics, Ecology, Drug Discovery, Evolution, Nanotechnology, Astrophysics, Neurobiology, Medicine, Multidisciplinary, Palaeobiology, Functional Genomics, Nature, Signal Transduction, Astronomy, DNA, Mitosis, Cell Differentiation, Video microscopy, Animals, Cell Signalling, Medical Research, Astrocyte, Glial Cell, Neurons, Rats, Radial Glia, Neocortex, Neuronal Migration, and Earth Science)
(Marine Biology, Neuroscience, Environmental Science, Geophysics, Physics, Materials Science, Quantum Physics, Developmental Biology, Immunology, Climate Change, Molecular Biology, Structural Biology, Genomics, RNA, Computational Biology, Transcriptomics, Biotechnology, Systems Biology, Cancer, Biology, Metabolomics, Cell Cycle, Proteomics, Ecology, Drug Discovery, Evolution, Nanotechnology, Astrophysics, Neurobiology, Medicine, Multidisciplinary, Palaeobiology, Functional Genomics, Nature, Signal Transduction, Astronomy, DNA, Mitosis, Cell Differentiation, Video microscopy, Animals, Cell Signalling, Medical Research, Astrocyte, Glial Cell, Neurons, Rats, Radial Glia, Neocortex, Neuronal Migration, and Earth Science)
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To obtain electrophysiological recordings in brain slices, sophisticated and expensive pieces of equipment can be used. However, costly microscope equipment with infrared differential interference contrast optics is not always necessary... more
To obtain electrophysiological recordings in brain slices, sophisticated and expensive pieces of equipment can be used. However, costly microscope equipment with infrared differential interference contrast optics is not always necessary or even desirable. For instance, obtaining a randomized unbiased sample in a given preparation would be better accomplished if cells were not directly visualized before recording. In addition, some preparations
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Large-scale surveys of single-cell gene expression have the potential to reveal rare cell populations and lineage relationships but require efficient methods for cell capture and mRNA sequencing. Although cellular barcoding strategies... more
Large-scale surveys of single-cell gene expression have the potential to reveal rare cell populations and lineage relationships but require efficient methods for cell capture and mRNA sequencing. Although cellular barcoding strategies allow parallel sequencing of single cells at ultra-low depths, the limitations of shallow sequencing have not been investigated directly. By capturing 301 single cells from 11 populations using microfluidics and analyzing single-cell transcriptomes across downsampled sequencing depths, we demonstrate that shallow single-cell mRNA sequencing (~50,000 reads per cell) is sufficient for unbiased cell-type classification and biomarker identification. In the developing cortex, we identify diverse cell types, including multiple progenitor and neuronal subtypes, and we identify EGR1 and FOS as previously unreported candidate targets of Notch signaling in human but not mouse radial glia. Our strategy establishes an efficient method for unbiased analysis and com...
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The majority of neurons in the adult neocortex are produced embryonically during a brief but intense period of neuronal proliferation. The radial glial cell, a transient embryonic cell type known for its crucial role in neuronal... more
The majority of neurons in the adult neocortex are produced embryonically during a brief but intense period of neuronal proliferation. The radial glial cell, a transient embryonic cell type known for its crucial role in neuronal migration, has recently been shown to function as a neuronal progenitor cell and appears to produce most cortical pyramidal neurons. Radial glial cell modulation
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Research Interests: Ethics, Technology, Stem Cells, Clinical Trial, Informed Consent, and 14 moreHuman embryonic stem cell, Health Policy, Stem Cell, Stem Cell Transplantation, Phase I clinical trial design, Biological Sciences, Cell line, Medical History, Humans, STEM, Embryo Research, Look Ahead, Ethical Issues, and Information Need
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Research Interests: Neuroscience, Stem Cells, Fluorescence Microscopy, Cell Cycle, Calcium, and 26 moreImmunohistochemistry, Multidisciplinary, Western blotting, Biological Sciences, Cerebral Cortex, Mice, Regulation of Gene Expression, Female, Animals, Cell Death, Feedback, Oscillations, Neurons, Dentate Gyrus, Lysine, Time Factors, Gonadotropin Releasing Hormone, Neocortex, Protein isoforms, Cell Proliferation, Cell Survival, Knockout Mice, Subventricular Zone, Glutamic Acid, Gamma-Aminobutyric Acid, and Neuroprotective Agents(Immunohistochemistry, Multidisciplinary, Western blotting, Biological Sciences, Cerebral Cortex, Mice, Regulation of Gene Expression, Female, Animals, Cell Death, Feedback, Oscillations, Neurons, Dentate Gyrus, Lysine, Time Factors, Gonadotropin Releasing Hormone, Neocortex, Protein isoforms, Cell Proliferation, Cell Survival, Knockout Mice, Subventricular Zone, Glutamic Acid, Gamma-Aminobutyric Acid, and Neuroprotective Agents)
(Immunohistochemistry, Multidisciplinary, Western blotting, Biological Sciences, Cerebral Cortex, Mice, Regulation of Gene Expression, Female, Animals, Cell Death, Feedback, Oscillations, Neurons, Dentate Gyrus, Lysine, Time Factors, Gonadotropin Releasing Hormone, Neocortex, Protein isoforms, Cell Proliferation, Cell Survival, Knockout Mice, Subventricular Zone, Glutamic Acid, Gamma-Aminobutyric Acid, and Neuroprotective Agents)
The development of glutamatergic synapses involves changes in the number and type of receptors present at the postsynaptic density. To elucidate molecular mechanisms underlying these changes, we combine in utero electroporation of... more
The development of glutamatergic synapses involves changes in the number and type of receptors present at the postsynaptic density. To elucidate molecular mechanisms underlying these changes, we combine in utero electroporation of constructs that alter the molecular composition of developing synapses with dual whole-cell electrophysiology to examine synaptic transmission during two distinct developmental stages. We find that SAP102 mediates synaptic trafficking of AMPA and NMDA receptors during synaptogenesis. Surprisingly, after synaptogenesis, PSD-95 assumes the functions of SAP102 and is necessary for two aspects of synapse maturation: the developmental increase in AMPA receptor transmission and replacement of NR2B-NMDARs with NR2A-NMDARs. In PSD-95/PSD-93 double-KO mice, the maturational replacement of NR2B- with NR2A-NMDARs fails to occur, and PSD-95 expression fully rescues this deficit. This study demonstrates that SAP102 and PSD-95 regulate the synaptic trafficking of distinct glutamate receptor subtypes at different developmental stages, thereby playing necessary roles in excitatory synapse development.
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Research Interests: Cognitive Science, Electrophysiology, Stem Cells, Patch-clamp and imaging techniques, Stem Cell Transplantation, and 14 moreCell Differentiation, Molecular and cellular biology, Cerebellum, Animals, Astrocyte, Astrocytes, Transcription Factor, Rats, Olfactory Bulb, Biological markers, Cellular and Molecular Neuroscience, Subventricular Zone, Neurosciences, and Interneurons
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... Calcium Dynamics of Neocortical Ventricular Zone Cells David F. Owens, Alexander C. Flint, Ryan S. Dammerman, Arnold R. Kriegstein Department of ... 2. Berninger B, Marty S, Zafra F, da Penha Berzaghi M, Thoenen H (1995): GABAergic... more
... Calcium Dynamics of Neocortical Ventricular Zone Cells David F. Owens, Alexander C. Flint, Ryan S. Dammerman, Arnold R. Kriegstein Department of ... 2. Berninger B, Marty S, Zafra F, da Penha Berzaghi M, Thoenen H (1995): GABAergic stimulation switches from enhancing to ...
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Neuronal migration disorders are often associated with intractable epilepsy. These cortical malformations are quite heterogeneous, suggesting that they may result from interference with a diverse set of processes during corticogenesis.... more
Neuronal migration disorders are often associated with intractable epilepsy. These cortical malformations are quite heterogeneous, suggesting that they may result from interference with a diverse set of processes during corticogenesis. Progress toward understanding the pathophysiologic basis of these disorders is coming from research into the basic mechanisms of corticogenesis, animal models of cortical malformations, and molecular genetic approaches to migration disorders.
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Transplantation of cells derived through the manipulation of pluripotent stem cells may involve great uncertainty and the possibility of serious risks. To develop guidelines for the ethical conduct of clinical trials using such stem... more
Transplantation of cells derived through the manipulation of pluripotent stem cells may involve great uncertainty and the possibility of serious risks. To develop guidelines for the ethical conduct of clinical trials using such stem cells. Review of literature on clinical trials ethics and clinical applications of stem cells; critical deliberation on potential guidelines. Such transplantation should be allowed in clinical practice only after clinical trials demonstrate efficacy and safety. These clinical trials should follow ethical principles that guide all clinical research. Additional requirements to strengthen trial design, coordinate scientific and ethics review, verify that participants understand key features of the trial, and ensure publication of findings are also warranted because of the highly innovative nature of the intervention, limited experience in humans, and the high hopes of patients who have no alternative effective treatments. These recommendations will need to be modified in light of actual experience with stem cell clinical trials. These recommendations will help guarantee that the efficacy and safety of innovative stem cell interventions will be rigorously established, while also protecting study participants.