Directing Astroglia from the Cerebral Cortex into Subtype Specific Functional Neurons
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{"title"=>"Directing astroglia from the cerebral cortex into subtype specific functional neurons", "type"=>"journal", "authors"=>[{"first_name"=>"Christophe", "last_name"=>"Heinrich", "scopus_author_id"=>"7006329969"}, {"first_name"=>"Robert", "last_name"=>"Blum", "scopus_author_id"=>"35291626900"}, {"first_name"=>"Sergio", "last_name"=>"Gascón", "scopus_author_id"=>"8955191700"}, {"first_name"=>"Giacomo", "last_name"=>"Masserdotti", "scopus_author_id"=>"14058542500"}, {"first_name"=>"Pratibha", "last_name"=>"Tripathi", "scopus_author_id"=>"57197259314"}, {"first_name"=>"Rodrigo", "last_name"=>"Sánchez", "scopus_author_id"=>"22935748900"}, {"first_name"=>"Steffen", "last_name"=>"Tiedt", "scopus_author_id"=>"36089174900"}, {"first_name"=>"Timm", "last_name"=>"Schroeder", "scopus_author_id"=>"7202054176"}, {"first_name"=>"Magdalena", "last_name"=>"Götz", "scopus_author_id"=>"7102031235"}, {"first_name"=>"Benedikt", "last_name"=>"Berninger", "scopus_author_id"=>"6603702149"}], "year"=>2010, "source"=>"PLoS Biology", "identifiers"=>{"pui"=>"358914455", "sgr"=>"77952948707", "issn"=>"15449173", "pmid"=>"20502524", "scopus"=>"2-s2.0-77952948707", "doi"=>"10.1371/journal.pbio.1000373", "isbn"=>"1545-7885 (Electronic)\\r1544-9173 (Linking)"}, "id"=>"796d3981-166c-318b-ae05-03b3828fbaf9", "abstract"=>"Astroglia from the postnatal cerebral cortex can be reprogrammed in vitro to generate neurons following forced expression of neurogenic transcription factors, thus opening new avenues towards a potential use of endogenous astroglia for brain repair. However, in previous attempts astroglia-derived neurons failed to establish functional synapses, a severe limitation towards functional neurogenesis. It remained therefore also unknown whether neurons derived from reprogrammed astroglia could be directed towards distinct neuronal subtype identities by selective expression of distinct neurogenic fate determinants. Here we show that strong and persistent expression of neurogenic fate determinants driven by silencing-resistant retroviral vectors instructs astroglia from the postnatal cortex in vitro to mature into fully functional, synapse-forming neurons. Importantly, the neurotransmitter fate choice of astroglia-derived neurons can be controlled by selective expression of distinct neurogenic transcription factors: forced expression of the dorsal telencephalic fate determinant neurogenin-2 (Neurog2) directs cortical astroglia to generate synapse-forming glutamatergic neurons; in contrast, the ventral telencephalic fate determinant Dlx2 induces a GABAergic identity, although the overall efficiency of Dlx2-mediated neuronal reprogramming is much lower compared to Neurog2, suggesting that cortical astroglia possess a higher competence to respond to the dorsal telencephalic fate determinant. Interestingly, however, reprogramming of astroglia towards the generation of GABAergic neurons was greatly facilitated when the astroglial cells were first expanded as neurosphere cells prior to transduction with Dlx2. Importantly, this approach of expansion under neurosphere conditions and subsequent reprogramming with distinct neurogenic transcription factors can also be extended to reactive astroglia isolated from the adult injured cerebral cortex, allowing for the selective generation of glutamatergic or GABAergic neurons. These data provide evidence that cortical astroglia can undergo a conversion across cell lineages by forced expression of a single neurogenic transcription factor, stably generating fully differentiated neurons. Moreover, neuronal reprogramming of astroglia is not restricted to postnatal stages but can also be achieved from terminally differentiated astroglia of the adult cerebral cortex following injury-induced reactivation.", "link"=>"http://www.mendeley.com/research/directing-astroglia-cerebral-cortex-subtype-specific-functional-neurons", "reader_count"=>309, "reader_count_by_academic_status"=>{"Unspecified"=>9, "Professor > Associate Professor"=>19, "Librarian"=>1, "Researcher"=>75, "Student > Doctoral Student"=>11, "Student > Ph. D. Student"=>83, "Student > Postgraduate"=>13, "Student > Master"=>39, "Other"=>10, "Student > Bachelor"=>28, "Lecturer"=>3, "Lecturer > Senior Lecturer"=>2, "Professor"=>16}, "reader_count_by_user_role"=>{"Unspecified"=>9, "Professor > Associate Professor"=>19, "Librarian"=>1, "Researcher"=>75, "Student > Doctoral Student"=>11, "Student > Ph. D. 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  • {"files"=>["https://ndownloader.figshare.com/files/423050", "https://ndownloader.figshare.com/files/423153", "https://ndownloader.figshare.com/files/423241", "https://ndownloader.figshare.com/files/423328", "https://ndownloader.figshare.com/files/423396", "https://ndownloader.figshare.com/files/423444", "https://ndownloader.figshare.com/files/423505", "https://ndownloader.figshare.com/files/423543", "https://ndownloader.figshare.com/files/423589"], "description"=>"<div><p>Astroglia from the postnatal cerebral cortex can be reprogrammed in vitro to generate neurons following forced expression of neurogenic transcription factors, thus opening new avenues towards a potential use of endogenous astroglia for brain repair. However, in previous attempts astroglia-derived neurons failed to establish functional synapses, a severe limitation towards functional neurogenesis. It remained therefore also unknown whether neurons derived from reprogrammed astroglia could be directed towards distinct neuronal subtype identities by selective expression of distinct neurogenic fate determinants. Here we show that strong and persistent expression of neurogenic fate determinants driven by silencing-resistant retroviral vectors instructs astroglia from the postnatal cortex in vitro to mature into fully functional, synapse-forming neurons. Importantly, the neurotransmitter fate choice of astroglia-derived neurons can be controlled by selective expression of distinct neurogenic transcription factors: forced expression of the dorsal telencephalic fate determinant neurogenin-2 (Neurog2) directs cortical astroglia to generate synapse-forming glutamatergic neurons; in contrast, the ventral telencephalic fate determinant Dlx2 induces a GABAergic identity, although the overall efficiency of Dlx2-mediated neuronal reprogramming is much lower compared to Neurog2, suggesting that cortical astroglia possess a higher competence to respond to the dorsal telencephalic fate determinant. Interestingly, however, reprogramming of astroglia towards the generation of GABAergic neurons was greatly facilitated when the astroglial cells were first expanded as neurosphere cells prior to transduction with Dlx2. Importantly, this approach of expansion under neurosphere conditions and subsequent reprogramming with distinct neurogenic transcription factors can also be extended to reactive astroglia isolated from the adult injured cerebral cortex, allowing for the selective generation of glutamatergic or GABAergic neurons. These data provide evidence that cortical astroglia can undergo a conversion across cell lineages by forced expression of a single neurogenic transcription factor, stably generating fully differentiated neurons. Moreover, neuronal reprogramming of astroglia is not restricted to postnatal stages but can also be achieved from terminally differentiated astroglia of the adult cerebral cortex following injury-induced reactivation.</p></div>", "links"=>[], "tags"=>["directing", "astroglia", "cerebral", "cortex", "subtype", "neurons"], "article_id"=>143533, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1000373.s001", "https://dx.doi.org/10.1371/journal.pbio.1000373.s002", "https://dx.doi.org/10.1371/journal.pbio.1000373.s003", "https://dx.doi.org/10.1371/journal.pbio.1000373.s004", "https://dx.doi.org/10.1371/journal.pbio.1000373.s005", "https://dx.doi.org/10.1371/journal.pbio.1000373.s006", "https://dx.doi.org/10.1371/journal.pbio.1000373.s007", "https://dx.doi.org/10.1371/journal.pbio.1000373.s008", "https://dx.doi.org/10.1371/journal.pbio.1000373.s009"], "stats"=>{"downloads"=>9, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Directing_Astroglia_from_the_Cerebral_Cortex_into_Subtype_Specific_Functional_Neurons/143533", "title"=>"Directing Astroglia from the Cerebral Cortex into Subtype Specific Functional Neurons", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-05-18 00:58:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/850825"], "description"=>"<p>(A–A”) Evidence for the astroglial origin of injury-induced neurospheres. (A) Bright field micrograph of a neurosphere obtained by culturing cells from the stab wound injured cerebral cortex of hGFAP-GFP mice. (A') Live GFP-fluorescence image of the same sphere shown in (A) demonstrates the astroglial nature of the neurosphere cells. (A”) Single plated GFP-positive neurosphere 1 d after plating. (B) Three wk post-infection with Neurog2 encoding retrovirus (DsRed), neurosphere cells from the same sphere shown in (A”) have differentiated into βIII tubulin-positive neurons (white) while losing GFP expression (arrowhead). In contrast, non-transduced astroglia continue expressing high levels of GFP driven from the hGFAP promoter (green). (C) Neurospheres derived from adult injured cortex of wild type mice were plated without dissociation as single neurosphere and subsequently transduced with Neurog2-IRES-DsRed. Double immunostaining for DsRed (red) and MAP2 (green) showing adult cortex-derived neurosphere cells 15 d after transduction with Neurog2 that differentiate into MAP2-positive neurons. (D) The micrograph shows a high magnification of a single MAP2-positive neuron derived from an adult cortex-derived neurosphere cell reprogrammed by Neurog2. Scale bars: C: 40 µm; D: 20 µm.</p>", "links"=>[], "tags"=>["cells", "derived", "reactive", "astroglia", "injured", "cerebral", "cortex", "differentiate", "neurons", "forced"], "article_id"=>521260, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g014", "stats"=>{"downloads"=>1, "page_views"=>72, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Neurosphere_cells_derived_from_reactive_astroglia_of_the_injured_adult_cerebral_cortex_differentiate_into_neurons_following_forced_expression_of_Neurog2_/521260", "title"=>"Neurosphere cells derived from reactive astroglia of the injured adult cerebral cortex differentiate into neurons following forced expression of Neurog2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:21:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/851089"], "description"=>"<p>(A) Fluorescence micrograph depicting a cluster of adult injured cortex-derived neurosphere cells transduced with a retrovirus encoding Neurog2 and DsRed that exhibit a neuronal morphology at 17 DPI. The white arrowhead indicates the tip of the recording pipette filled with DsRed. (A') The graph shows repetitive firing of action potentials in response to step-current injection in the neuron marked by the asterisk in (A). (B) Double immunocytochemistry for MAP2 (red) and vGluT1 (green) shows a dense labelling of vGluT1-positive puncta that outline the MAP2-positive processes emanating from adult cortex-derived neurosphere cells reprogrammed by Neurog2 at 28 DPI. (C) Massive expression of vGluT1-positive puncta (green) outlining the cell body and the processes of two adult cortex-derived neurosphere cells transduced with Neurog2 (red) at 28 DPI. (D) The fluorescence micrograph depicts a Neurog2-expressing neurosphere cell 19 DPI exhibiting a dense punctuate staining for synapsin, indicating the presence of synapses impinging onto this neuron. (E) The graph depicts spontaneous synaptic activity recorded from adult injured cortex-derived neurosphere cells transduced with Neurog2 at 28 DPI. The enlarged trace shows individual synaptic events displaying fast decay time kinetics typical of glutamatergic currents. (F–F”) Spontaneous activity can be blocked by CNQX demonstrating that it is driven by glutamatergic synaptic transmission. Scale bars: B: 25 µm; C, D: 12 µm.</p>", "links"=>[], "tags"=>["astroglia", "injured", "cortex", "expanded", "neurospheres", "neurons", "forced"], "article_id"=>521530, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g015", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reactive_astroglia_from_the_adult_injured_cortex_expanded_as_neurospheres_generate_functional_neurons_upon_forced_expression_of_Neurog2_/521530", "title"=>"Reactive astroglia from the adult injured cortex expanded as neurospheres generate functional neurons upon forced expression of Neurog2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/850342"], "description"=>"<p>(A) Postnatal cortical astroglia were first expanded as neurospheres and subsequently transduced with a retrovirus encoding Neurog2 and DsRed. Immunostaining for DsRed reveals that virtually all astroglia-derived neurosphere cells differentiate into neurons upon forced expression of Neurog2 at 30 DPI. (B) Micrograph depicting vGluT1 immunocytochemistry of the same culture shown in (A). Note the massive expression of vGluT1-positive puncta indicating that the majority of the Neurog2-expressing neurons acquire a glutamatergic identity. (C) High magnification view of a single Neurog2-reprogrammed cell. Double immunostaining for DsRed (red) and vGluT1 (green) illustrates the dense labelling and the distribution of the vGluT1-positive puncta. Insets show high magnification views of the boxed areas. (D) Fate-mapping analysis using postnatal cortex of tamoxifen induced GLAST::CreERT2/Z/EG mice corroborates the astroglial origin of the cells reprogrammed by Neurog2. The fluorescence micrograph depicts a GFP-positive cell derived from a fate-mapped astroglia and exhibiting a neuronal morphology following transduction with Neurog2 at 14 DPI (arrow). Note the non-reprogrammed GFP-positive astroglial cell in absence of Neurog2 transduction (arrowhead). (E–F) Fluorescence micrographs depicting two fate-mapped GFP-positive neurons (E) co-expressing DsRed at 13 DPI (F), thus indicating reprogramming by Neurog2. The red and the black asterisks mark the presynaptic and the postsynaptic neurons, respectively. (G) Dual recording revealing the glutamatergic nature of the stimulated presynaptic neuron. The presynaptic neuron is step-depolarised in voltage clamp (pair pulse stimulation, lower red trace) evoking inward synaptic currents in a nearby postsynaptic neuron that are completely abolished by CNQX (upper black traces; each trace represents an average of 10 single responses including failures). The upper red trace shows the recovery of the glutamatergic synaptic responses after washout of CNQX, perfectly overlaying the responses prior to CNQX treatment. Scale bars: A, B: 80 µm; C: 11 µm; Insets in C: 5 µm; D: 40 µm.</p>", "links"=>[], "tags"=>["cortical", "astroglia", "expanded", "neurospheres", "subsequently", "reprogrammed", "neurog2", "synapse-forming", "glutamatergic"], "article_id"=>520776, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g012", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Postnatal_cortical_astroglia_expanded_as_neurospheres_and_subsequently_reprogrammed_by_Neurog2_generate_synapse_forming_glutamatergic_neurons_/520776", "title"=>"Postnatal cortical astroglia expanded as neurospheres and subsequently reprogrammed by Neurog2 generate synapse-forming glutamatergic neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:12:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/850127"], "description"=>"<p>(A) Postnatal cortical astroglia were first expanded as neurospheres and subsequently transduced with a retrovirus encoding Dlx2 and DsRed. Double immunocytochemistry for DsRed (red) and vGaT (green) reveals that astroglia-derived neurosphere cells reprogrammed by Dlx2 exhibit a dense labelling of vGaT-positive puncta outlining their soma and their dendrites, indicating that Dlx2-reprogrammed neurons acquire a GABAergic identity (30 DPI). (B) High magnification view of a single astroglia-derived neurosphere cell transduced with Dlx2 illustrating the massive expression and the distribution of vGaT-positive puncta. The inset shows a high magnification view of the boxed area. (C–D) The fluorescence micrographs depict a fate-mapped, GFP-positive neuron (C, asterisk) co-expressing DsRed at 14 DPI (D, asterisk), indicating forced expression of Dlx2. (E) Step-depolarisation of the neuron shown in (C) and (D) evokes a GABAergic autaptic response (black trace) that is blocked by bicuculline (10 µM, red trace). Scale bars: A: 20 µm; B: 7 µm; Inset in B: 2 µm.</p>", "links"=>[], "tags"=>["postnatal", "astroglia", "expanded", "neurosphere", "cells", "gabaergic", "neurons", "forced"], "article_id"=>520565, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g011", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reprogramming_of_postnatal_astroglia_expanded_as_neurosphere_cells_into_functional_GABAergic_neurons_following_forced_expression_of_Dlx2_/520565", "title"=>"Reprogramming of postnatal astroglia expanded as neurosphere cells into functional GABAergic neurons following forced expression of Dlx2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:09:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/849848"], "description"=>"<p>(A–A') Fluorescence micrographs depict two cells double-positive for GFP (A) and DsRed (A') indicating co-expression of Mash1 (Mash1-IRES-GFP) and Dlx2 (Dlx2-IRES-DsRed), respectively. (A”) Depolarizing current injection into the neuron marked by the asterisk in (A) and (A') revealed a firing pattern classified as stuttering. (B) The histogram shows the percentage of βIII tubulin-positive neurons amongst all single or co-transduced astroglial cells. Note the significant enhancement of neurogenesis following co-expression of Mash1 and Dlx2. (C) The graph plots the input resistance values over time (MΩ) of astroglia-derived neurons reprogrammed by Dlx2 alone or Mash1 and Dlx2 in combination. Note that the co-expressing cells exhibit lower input resistances suggestive of a faster pace of maturation.</p>", "links"=>[], "tags"=>["mash1", "dlx2", "neurogenesis", "maturation"], "article_id"=>520294, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g009", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Co_expression_of_Mash1_and_Dlx2_promotes_neurogenesis_and_maturation_following_reprogramming_/520294", "title"=>"Co-expression of Mash1 and Dlx2 promotes neurogenesis and maturation following reprogramming.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:04:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/849552"], "description"=>"<p>(A) Fluorescence micrograph depicts a GFP-positive neuron derived from a fate-mapped astroglia, prepared from postnatal cortex of tamoxifen induced GLAST::CreERT2/Z/EG mice that has been reprogrammed by forced expression of Dlx2. (A') DsRed expression in the same cell at 20 DPI indicates prior reprogramming by Dlx2. (A”) Step-current injection in current clamp in the cell shown in (A) and (A') results in a single action potential. (B) Fluorescence micrograph depicts a GFP-positive neuron derived from a fate-mapped astroglia, prepared from postnatal cortex of tamoxifen induced GLAST::CreERT2/Z/EG mice that has been reprogrammed by forced expression of Dlx2. (B') DsRed expression in the same cell at 17 DPI indicates prior reprogramming by Dlx2. (B”) Step-current injection in current clamp in the cell shown in (B) and (B') results in repetitive firing of action potentials. Note the high action potential firing rate undergoing little adaptation (approximately 80 Hz). (C–C”) Traces show recordings from a Dlx2-reprogrammed cell classified as a low-threshold burst-spiking neuron. (C) Depolarizing current injection at a holding potential of −62 mV resulted in a burst discharge, while a hyperpolarizing current injection (red trace) induced a rebound burst following the relief from hyperpolarisation. (C') In the presence of TTX, burst-spiking was suppressed revealing a long-lasting spike, presumably mediated by low-threshold calcium channels. (C”) Depolarizing current injection at a more positive holding potential (−44 mV) resulted in repetitive firing instead of a burst discharge typical of low-threshold burst spiking interneurons. (D) Fluorescence micrograph depicting neurons derived from Dlx2-transduced astroglia at 28 DPI. (E) The graph depicts spontaneous synaptic events recorded from the astroglia-derived neuron marked by the asterisk in (D). The enlarged trace shows a single event displaying a slow decay time typical of GABAergic synaptic events. (F) Step-depolarisation in voltage clamp of a Dlx2-reprogrammed astroglia evokes a GABAergic autaptic response at 30 DPI (lower black trace), which is blocked by the GABA<sub>A</sub> receptor antagonist bicuculline (10 µM, upper black trace). The red trace shows the recovery of the evoked autaptic response after washout of bicuculline.</p>", "links"=>[], "tags"=>["cortical", "astroglia", "reprogrammed", "forced", "dlx2", "synapse-forming", "gabaergic"], "article_id"=>520001, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g007", "stats"=>{"downloads"=>5, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Postnatal_cortical_astroglia_reprogrammed_by_forced_expression_of_Dlx2_give_rise_to_synapse_forming_GABAergic_neurons_/520001", "title"=>"Postnatal cortical astroglia reprogrammed by forced expression of Dlx2 give rise to synapse-forming GABAergic neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:00:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/849987"], "description"=>"<p>Cells from the E12.5 cerebral cortex (white bars), astroglia cultured under adherent conditions (7 d, black bars), and astroglia cultured under neurosphere conditions (7 d, red bars) were compared for the expression of several genes by quantitative RT-PCR. The expression of the mRNAs encoding GFAP (A), S100β (B), Aldh1L1 <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000373#pbio.1000373-Cahoy1\" target=\"_blank\">[37]</a> (C), Glu1 (D), Glt-1 (E), βIII tubulin (F), Neurog2 (G), Emx1 (H), Emx2 (I), and Sox2 (J) was normalized to the respective mRNA amount estimated for E12.5 cerebral cortex tissue and plotted as fold expression.</p>", "links"=>[], "tags"=>["molecular", "markers", "shows", "astroglia", "cultured", "neurosphere", "conditions", "astroglial", "up-regulating"], "article_id"=>520427, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g010", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_analysis_of_molecular_markers_shows_that_astroglia_cultured_under_neurosphere_conditions_keep_an_astroglial_signature_while_up_regulating_Sox2_/520427", "title"=>"Expression analysis of molecular markers shows that astroglia cultured under neurosphere conditions keep an astroglial signature, while up-regulating Sox2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:07:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/850581"], "description"=>"<p>(A) The fluorescence micrograph depicts GFP-positive neurons derived from fate-mapped astroglia prepared from the postnatal cortex of tamoxifen-induced GLAST::CreERT2/Z/EG mice, that were first expanded as neurospheres and subsequently reprogrammed by forced expression of Neurog2. Arrowheads show the four neurons that are analysed in (C–E). (B) DsRed expression in the same cells shown in (A) indicating neuronal reprogramming by Neurog2. (C–E) The graphs show spontaneous Ca<sup>2+</sup> transients occurring synchronously in the four recorded neurons shown in (A) and (B), that are totally abolished in the presence of CNQX/AP5 (D, 10 µM each) and re-emerge following washout of the drugs (E). The trace of each individual neuron is shown in a different colour.</p>", "links"=>[], "tags"=>["imaging", "experiments", "fate-mapped", "postnatal", "astroglia", "expanded", "neurospheres", "subsequently", "transduced"], "article_id"=>521020, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g013", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Calcium_imaging_experiments_of_fate_mapped_postnatal_astroglia_expanded_as_neurospheres_and_subsequently_transduced_with_Neurog2_/521020", "title"=>"Calcium imaging experiments of fate-mapped postnatal astroglia expanded as neurospheres and subsequently transduced with Neurog2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:17:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/849003"], "description"=>"<p>(A) Fluorescence micrograph depicting a GFP-positive neuron derived from a fate-mapped astroglia, prepared from postnatal cortex of tamoxifen-induced GLAST::CreERT2/Z/EG mice, 14 d after transduction with Neurog2-DsRed. The inset shows control untransduced GFP-positive astroglia. (B) DsRed expression in the same cell indicating forced expression of Neurog2. (C) Step-current injection into the cell shown in (A) and (B) results in repetitive firing of action potentials. (D–E) Fluorescence micrographs depicting another GFP-positive neuron, derived from a fate-mapped astroglia, following Neurog2-induced reprogramming 19 d after transduction. (F) Step-depolarisation at 1 Hz of the neuron shown in (D) and (E) evokes an autaptic response exhibiting a short decay time (90%–10%) typical of glutamatergic synaptic transmission (5.2 ms). The inset shows a single response evoked at 0.05 Hz revealing both an autaptic and a polysynaptic response (asterisk) due to recruitment of other neurons in the cultured network, indicating the excitatory nature of the fate-mapped reprogrammed neuron. (G–H) Another example of a GFP-positive neuron derived from a fate-mapped astroglia following Neurog2-induced reprogramming 27 DPI. The inset in (H) shows an enlargement of the boxed area revealing a DsRed-positive axon (arrowheads) originating from another DsRed-positive neuron and meandering along the dendrites and the soma of the recorded cell, after the patch pipette had been withdrawn and the cell died. (I) Step-depolarisation of the neuron shown in (G) and (H) evokes a sequence of both autaptic and polysynaptic responses. The black traces show individual autaptic responses observed in isolation when evoked at 1 Hz to eliminate polysynaptic components (the average trace is shown in red). The autapse exhibited a short decay time (90%–10%) typical of glutamatergic synaptic transmission (7.7 ms). The inset shows two individual responses evoked at 0.05 Hz (black and red traces) revealing both autaptic and polysynaptic responses (asterisk) due to recruitment of other neurons in the cultured network, indicating the excitatory nature of the fate-mapped reprogrammed neuron. (J–K) Expression of the vesicular glutamate transporter 1 (vGluT1) by fate-mapped postnatal astroglia reprogrammed by Neurog2. (J) Micrograph depicting a GFP and DsRed double-positive neuron derived from a fate-mapped astroglia, 27 d after transduction with a retrovirus encoding Neurog2 and DsRed. Note the DsRed-negative fate-mapped astrocyte. (K) Immunocytochemistry for vGluT1 reveals that the fate-mapped astroglia-derived neuron reprogrammed by Neurog2 exhibits a dense labelling of vGluT1-positive puncta outlining its cell body and dendrites. The insets show higher magnification views of the soma and dendrites illustrating the punctuate staining for vGluT1. Scale bars: J-K: 30 µm.</p>", "links"=>[], "tags"=>["cortical", "astroglia", "reprogrammed", "forced", "neurog2", "synaptic"], "article_id"=>519449, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fate_mapped_cortical_astroglia_reprogrammed_by_forced_expression_of_Neurog2_establish_functional_synaptic_connections_/519449", "title"=>"Fate-mapped cortical astroglia reprogrammed by forced expression of Neurog2 establish functional synaptic connections.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 02:37:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/849213"], "description"=>"<p>Time-lapse sequence of an astroglia culture transfected with a retroviral plasmid encoding Neurog2 and DsRed. The respective time points are shown in the individual panels (from 0 d 00 h to 4 d 12 h). (A–C) Bright field micrographs show high magnification views of an astroglial culture during the first 18 h of continuous time-lapse imaging. The arrow marks a cell that was subsequently found to be transfected (D–H). The asterisks mark other astroglial cells in the field of view for orientation. (D–H) DsRed-fluorescence micrographs depicting the same cell marked by the arrow in (A–C). Note the onset of weak DsRed expression at 18 h (D). The fluorescence micrographs at subsequent time points show the progressive reprogramming of the transfected astrocyte into a neuron which is completed by 4 d 12 h. Note that during the entire imaging period the cell giving rise to a neuron did not undergo cell cycle division.</p>", "links"=>[], "tags"=>["neuronal", "Reprogramming", "postnatal", "astroglia", "forced"], "article_id"=>519658, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_division_is_not_a_requirement_for_neuronal_reprogramming_of_postnatal_astroglia_by_forced_expression_of_Neurog2_/519658", "title"=>"Cell division is not a requirement for neuronal reprogramming of postnatal astroglia by forced expression of Neurog2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 02:40:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/849351"], "description"=>"<p>(A) Representative example of a GFP-positive neuron derived from a fate-mapped cortical astroglia, originating from postnatally induced GLAST::CreERT2/Z/EG mice, reprogrammed by forced expression of Dlx2 and shown at 22 DPI. (A') DsRed expression in the same cell indicating forced expression of Dlx2. (A”) The same astroglia-derived neuron as shown in (A) and (A′) is immunoreactive for the mature neuronal marker MAP2. (B–B') Triple immunostaining of a Dlx2-transduced cell positive for the neuronal marker βIII tubulin (B, green), DsRed (B, red), and GAD67 (B', white). (C) Double immunostaining of a Dlx2-transduced cell positive for DsRed (inset, red) and calretinin (green). (D) Double immunostaining for DsRed (red) and vGaT (green) showing an astroglia-derived neuron reprogrammed by forced expression of Dlx2 at 30 DPI, that exhibits a dense labelling of vGaT-positive puncta outlining its soma and processes. Scale bars: A–A″: 10 µm.</p>", "links"=>[], "tags"=>["astroglia", "postnatal", "cortex", "reprogrammed", "neurons", "forced"], "article_id"=>519800, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g006", "stats"=>{"downloads"=>3, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fate_mapped_astroglia_from_the_postnatal_cortex_can_be_reprogrammed_to_generate_neurons_by_forced_expression_of_Dlx2_/519800", "title"=>"Fate-mapped astroglia from the postnatal cortex can be reprogrammed to generate neurons by forced expression of Dlx2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 02:43:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/848728"], "description"=>"<p>(A–A') The histograms show the percentage of GFP reporter-positive cells from GLAST::CreERT2/Z/EG mice immunoreactive for the astroglial marker GFAP, oligodendroglial markers NG2/O4, and the neuronal marker βIII tubulin 1 d after plating (A) and 9–21 d after plating (A'), respectively. (B–B”) Cortical astroglia transduced with control retrovirus remain in the glial lineage. (B) The micrograph depicts GFP-positive, fate-mapped astroglia derived from postnatally induced GLAST::CreERT2/Z/EG mice. (B'–B”) Micrographs of the same field of view as shown in (B) showing that fate-mapped astroglia transduced with a control retrovirus encoding DsRed only (pCAG-IRES-DsRed) exhibit a glial morphology and express GFAP (B”). (C) Representative example of a GFP-positive neuron, i.e. derived from a fate-mapped astroglia, prepared from the postnatal cortex of tamoxifen-induced GLAST::CreERT2/Z/EG mice. (C') DsRed expression in the same cell indicating forced expression of Neurog2. (C”) The same astroglia-derived neuron as shown in (C) and (C') is immunoreactive for the mature neuronal marker MAP2 (27 DPI). (D–D') Direct visualisation of Neurog2-induced reprogramming of fate-mapped astroglia by time-lapse video microscopy. (D) Sequence of bright field images, overlaid with GFP reporter fluorescence, depicting the same field of view over the time course of 5 d as indicated in the corresponding panels below in (D'). The arrow points to a reporter-positive cell that divided once giving rise to two daughter cells that subsequently underwent reprogramming into neurons. The arrowhead points to another fate-mapped reprogrammed cell that entered the field of view at a later time point. (D') Corresponding sequence of DsRed fluorescence images taken at the same time points as the bright field images shown in (D). Note the expression of DsRed (encoded by Neurog2-IRES-DsRed) in the fate-mapped cell (arrow). Note that besides fate-mapped cells, several other Neurog2-transduced cells also became reprogrammed into neurons. Scale bars: B–B”: 57 µm; C–C”: 26 µm.</p>", "links"=>[], "tags"=>["astroglia", "postnatal", "cortex", "reprogrammed", "neurons", "forced"], "article_id"=>519173, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g003", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fate_mapped_astroglia_from_the_postnatal_cortex_can_be_reprogrammed_to_generate_neurons_following_forced_expression_of_Neurog2_/519173", "title"=>"Fate-mapped astroglia from the postnatal cortex can be reprogrammed to generate neurons following forced expression of Neurog2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 02:32:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/848300"], "description"=>"<p>(A–B) Triple immunostaining for DsRed (red), MAP2 (blue), and vGluT1 (green) reveals that astroglia-derived neurons reprogrammed by Neurog2 exhibit a dense labelling of vGluT1-positive puncta outlining their soma and their MAP2-positive processes (27 DPI). (B) High magnification of a single astroglia-derived neuron illustrating the high density and the distribution of vGluT1-immunoreactive puncta. Insets show higher magnification views of the boxed areas. (C) The micrograph depicts two Neurog2-transduced cells exhibiting a neuronal morphology (28 DPI). The black and red asterisks mark the presynaptic and postsynaptic neurons recorded in panel (D), respectively. (D) Step-depolarisation of a presynaptic neuron evokes both an autaptic (upper red trace) and a monosynaptic response (delay 2 ms) in a nearby postsynaptic neuron (lower red trace). Both the synaptic and the autaptic responses were completely abolished in the presence of the AMPA/kainate receptor antagonist CNQX (10 µM; black traces), demonstrating the glutamatergic nature of the presynaptic neuron. (E) Triple immunostaining for DsRed (red), CaMKIIα (green), and vGluT1 (white). (F–F') High magnification views of the area boxed in (E) showing dendritic spines (red arrowheads) as revealed by CaMKIIα immunoreactivity (F), which are covered by vGluT1-positive puncta (F', red arrowheads), suggestive of sites of synaptic contact. Scale bars: A: 40 µm; B: 20 µm; insets in B: 5 µm; E: 26 µm; F–F': 5 µm.</p>", "links"=>[], "tags"=>["cortical", "astroglia", "reprogrammed", "forced", "neurog2", "synapse-forming", "glutamatergic"], "article_id"=>518742, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g001", "stats"=>{"downloads"=>6, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Postnatal_cortical_astroglia_reprogrammed_by_forced_expression_of_Neurog2_give_rise_to_synapse_forming_glutamatergic_neurons_/518742", "title"=>"Postnatal cortical astroglia reprogrammed by forced expression of Neurog2 give rise to synapse-forming glutamatergic neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 02:25:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/849753"], "description"=>"<p>Note that combined expression of Mash1 and Dlx2 results in a higher fraction of neurons exhibiting more mature interneuron firing patterns compared to Dlx2 alone.</p>", "links"=>[], "tags"=>["firing", "patterns", "astroglia", "reprogrammed", "forced", "dlx2", "mash1"], "article_id"=>520198, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g008", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Classification_of_action_potential_firing_patterns_of_astroglia_reprogrammed_by_forced_expression_of_Dlx2_alone_or_Mash1_and_Dlx2_in_combination_/520198", "title"=>"Classification of action potential firing patterns of astroglia reprogrammed by forced expression of Dlx2 alone or Mash1 and Dlx2 in combination.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 00:03:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/848530"], "description"=>"<p>(A) Spontaneous synaptic activity recorded in cultures of Neurog2-reprogrammed astroglia at 28 DPI. The upper trace shows two large barrages of synaptic currents that are likely to underlie the spontaneous Ca<sup>2+</sup> transients shown in (B–B”). The enlarged traces below show individual synaptic events during barrage-free periods of recording. (B–B”) Calcium imaging experiments performed at 29 DPI reveal self-driven network oscillations. (B) Micrograph depicting two DsRed-positive neurons (arrowheads) derived from Neurog2-reprogrammed astroglia recorded in (B'–B”). Cultures were incubated with the calcium-sensitive probe Oregon Green BAPTA1. (B') The graphs depict increases in Oregon Green fluorescence intensity over time (ΔF/F0) that reveal spontaneous and synchronous raises in free intracellular Ca<sup>2+</sup> concentration in the two neurons shown in (B). (B”) These raises in Ca<sup>2+</sup> concentration are completely abolished in the presence of CNQX (10 µM).</p>", "links"=>[], "tags"=>["derived", "neurog2-reprogrammed", "astroglia", "spontaneous", "excitatory"], "article_id"=>518975, "categories"=>["Neuroscience", "Cell Biology", "Developmental Biology"], "users"=>["Christophe Heinrich", "Robert Blum", "Sergio Gascón", "Giacomo Masserdotti", "Pratibha Tripathi", "Rodrigo Sánchez", "Steffen Tiedt", "Timm Schroeder", "Magdalena Götz", "Benedikt Berninger"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1000373.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Neurons_derived_from_Neurog2_reprogrammed_astroglia_generate_spontaneous_excitatory_network_activity_/518975", "title"=>"Neurons derived from Neurog2-reprogrammed astroglia generate spontaneous excitatory network activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-05-18 02:29:35"}

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  • {"unique-ip"=>"24", "full-text"=>"25", "pdf"=>"9", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"12", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
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Relative Metric

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