The Experts below are selected from a list of 2010 Experts worldwide ranked by ideXlab platform
John L.r. Rubenstein - One of the best experts on this subject based on the ideXlab platform.
-
the zinc finger transcription factor sp9 is required for the development of striatopallidal projection neurons
Cell Reports, 2016Co-Authors: Qiangqiang Zhang, Yue Zhang, Chunyang Wang, Qifei Liang, Zhidong Liu, Yan You, Ying Mao, Bin Chen, Zhiqi Xiong, John L.r. RubensteinAbstract:Striatal medium-sized spiny neurons (MSNs), composed of striatonigral and striatopallidal neurons, are derived from the lateral Ganglionic Eminence (LGE). We find that the transcription factor Sp9 is expressed in LGE progenitors that generate nearly all striatal MSNs and that Sp9 expression is maintained in postmitotic striatopallidal MSNs. Sp9-null mice lose most striatopallidal MSNs because of decreased proliferation of striatopallidal MSN progenitors and increased Bax-dependent apoptosis, whereas the development of striatonigral neurons is largely unaffected. ChIP qPCR provides evidence that Ascl1 directly binds the Sp9 promoter. RNA-seq and in situ hybridization reveal that Sp9 promotes expression of Adora2a, P2ry1, Gpr6, and Grik3 in the LGE and striatum. Thus, Sp9 is crucial for the generation, differentiation, and survival of striatopallidal MSNs.
-
otx2 transcription factor controls regional patterning within the medial Ganglionic Eminence and regional identity of the septum
Cell Reports, 2015Co-Authors: Renee V Hoch, Susan Lindtner, James D Price, John L.r. RubensteinAbstract:Summary The Otx2 homeodomain transcription factor is essential for gastrulation and early neural development. We generated Otx2 conditional knockout (cKO) mice to investigate its roles in telencephalon development after neurulation (approximately embryonic day 9.0). We conducted transcriptional profiling and in situ hybridization to identify genes de-regulated in Otx2 cKO ventral forebrain. In parallel, we used chromatin immunoprecipitation sequencing to identify enhancer elements, the OTX2 binding motif, and de-regulated genes that are likely direct targets of OTX2 transcriptional regulation. We found that Otx2 was essential in septum specification, regulation of Fgf signaling in the rostral telencephalon, and medial Ganglionic Eminence (MGE) patterning, neurogenesis, and oligodendrogenesis. Within the MGE, Otx2 was required for ventral, but not dorsal, identity, thus controlling the production of specific MGE derivatives.
-
soluble guanylate cyclase generation of cgmp regulates migration of mge neurons
The Journal of Neuroscience, 2013Co-Authors: Shyamali Mandal, Amelia Stanco, Emmanuel S Buys, Grigori Enikolopov, John L.r. RubensteinAbstract:Here we have provided evidence that nitric oxide-cyclic GMP (NO-cGMP) signaling regulates neurite length and migration of immature neurons derived from the medial Ganglionic Eminence (MGE). Dlx1/2−/− and Lhx6−/− mouse mutants, which exhibit MGE interneuron migration defects, have reduced expression of the gene encoding the α subunit of a soluble guanylate cyclase (Gucy1A3). Furthermore, Dlx1/2−/− mouse mutants have reduced expression of NO synthase 1 (NOS1). Gucy1A3−/− mice have a transient reduction in cortical interneuron number. Pharmacological inhibition of soluble guanylate cyclase and NOS activity rapidly induces neurite retraction of MGE cells in vitro and in slice culture and robustly inhibits cell migration from the MGE and caudal Ganglionic Eminence. We provide evidence that these cellular phenotypes are mediated by activation of the Rho signaling pathway and inhibition of myosin light chain phosphatase activity.
-
dlx1 2 dependent expression of zfhx1b sip1 zeb2 regulates the fate switch between cortical and striatal interneurons
Neuron, 2013Co-Authors: Gabriel L Mckinsey, Susan Lindtner, Axel Visel, Len A. Pennacchio, Brett Trzcinski, Danny Huylebroeck, Yujiro Higashi, John L.r. RubensteinAbstract:Mammalian pallial (cortical and hippocampal) and striatal interneurons are both generated in the embryonic subpallium, including the medial Ganglionic Eminence (MGE). Herein we demonstrate that the Zfhx1b (Sip1, Zeb2) zinc finger homeobox gene is required in the MGE, directly downstream of Dlx1&2, to generate cortical interneurons that express Cxcr7, MafB, and cMaf. In its absence, Nkx2-1 expression is not repressed, and cells that ordinarily would become cortical interneurons appear to transform toward a subtype of GABAergic striatal interneurons. These results show that Zfhx1b is required to generate cortical interneurons, and suggest a mechanism for the epilepsy observed in humans with Zfhx1b mutations (Mowat-Wilson syndrome).
-
the progenitor zone of the ventral medial Ganglionic Eminence requires nkx2 1 to generate most of the globus pallidus but few neocortical interneurons
The Journal of Neuroscience, 2010Co-Authors: Pierre Flandin, Shioko Kimura, John L.r. RubensteinAbstract:We show that most globus pallidus neurons, but very few neocortical interneurons, are generated from the ventral medial Ganglionic Eminence and dorsal preoptic area based on fate mapping using an Shh-Cre allele. The Shh-expressing subpallial lineage produces parvalbumin+ GABAergic neurons, ChAT+ cholinergic neurons, and oligodendrocytes. Loss of Nkx2-1 function from the Shh-expressing domain eliminated most globus pallidus neurons, whereas most cortical and striatal interneurons continued to be generated, except for striatal cholinergic neurons. Finally, our analysis provided evidence for a novel cellular component (Nkx2-1−;Npas1+) of the globus pallidus.
Klas Wictorin - One of the best experts on this subject based on the ideXlab platform.
-
neuronal differentiation following transplantation of expanded mouse neurosphere cultures derived from different embryonic forebrain regions
Experimental Neurology, 2003Co-Authors: Cecilia Eriksson, Anders Bjorklund, Klas WictorinAbstract:In vitro, expanded neurospheres exhibit multipotent properties and can differentiate into neurons, astrocytes and oligodendrocytes. In vivo, cells from neurospheres derived from mouse fetal forebrain have previously been reported to predominantly differentiate into glial cells, and not into neurons. Here we isolated stem/progenitor cells from E13.5 lateral Ganglionic Eminence (LGE), medial Ganglionic Eminence (MGE) and cortical primordium, of a green fluorescent protein (GFP)-actin transgenic mouse. Free-floating neurospheres were expanded in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) and implanted after five to six passages into the striatum, hippocampus and cortex of neonatal rats. Cell suspensions of primary LGE tissue were prepared and grafted in parallel. Grafted cells derived from the primary tissue displayed widespread incorporation into all regions, as visualized with the mouse-specific antibody M2, or mouse satellite DNA in situ hybridization, and differentiated into both neurons, astrocytes and oligodendrocytes. Grafts of neurosphere cells derived from the LGE, MGE and cortical primordium differentiated primarily into astrocytes, but contained low but significant numbers of GFP-immunoreactive neurons. Neurons derived from LGE neurospheres were of three types: cells with the morphology of medium-sized densely spiny projection neurons in the striatum; cells with interneuron-like morphologies in striatum, cortex and hippocampus; and cells integrating into SVZ and migrating along the RMS to the olfactory bulb. MGE- or cortical primordium-derived neurospheres differentiated into interneuron-like cells in both striatum and hippocampus. The results demonstrate the ability of in vitro expanded neural stem/progenitor cells to generate both neurons and glia after transplantation into neonatal recipients, and differentiate in a region-specific manner into mature neurons with morphological features characteristic for each target site.
-
neuronal differentiation following transplantation of expanded mouse neurosphere cultures derived from different embryonic forebrain regions
Experimental Neurology, 2003Co-Authors: Cecilia Eriksson, Anders Bjorklund, Klas WictorinAbstract:In vitro, expanded neurospheres exhibit multipotent properties and can differentiate into neurons, astrocytes and oligodendrocytes. In vivo, cells from neurospheres derived from mouse fetal forebrain have previously been reported to predominantly differentiate into glial cells, and not into neurons. Here we isolated stem/progenitor cells from E13.5 lateral Ganglionic Eminence (LGE), medial Ganglionic Eminence (MGE) and cortical primordium, of a green fluorescent protein (GFP)-actin transgenic mouse. Free-floating neurospheres were expanded in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) and implanted after five to six passages into the striatum, hippocampus and cortex of neonatal rats. Cell suspensions of primary LGE tissue were prepared and grafted in parallel. Grafted cells derived from the primary tissue displayed widespread incorporation into all regions, as visualized with the mouse-specific antibody M2, or mouse satellite DNA in situ hybridization, and differentiated into both neurons, astrocytes and oligodendrocytes. Grafts of neurosphere cells derived from the LGE, MGE and cortical primordium differentiated primarily into astrocytes, but contained low but significant numbers of GFP-immunoreactive neurons. Neurons derived from LGE neurospheres were of three types: cells with the morphology of medium-sized densely spiny projection neurons in the striatum; cells with interneuron-like morphologies in striatum, cortex and hippocampus; and cells integrating into SVZ and migrating along the RMS to the olfactory bulb. MGE- or cortical primordium-derived neurospheres differentiated into interneuron-like cells in both striatum and hippocampus. The results demonstrate the ability of in vitro expanded neural stem/progenitor cells to generate both neurons and glia after transplantation into neonatal recipients, and differentiate in a region-specific manner into mature neurons with morphological features characteristic for each target site.
Stewart A. Anderson - One of the best experts on this subject based on the ideXlab platform.
-
spatial and temporal bias in the mitotic origins of somatostatin and parvalbumin expressing interneuron subgroups and the chandelier subtype in the medial Ganglionic Eminence
Cerebral Cortex, 2012Co-Authors: Melis Inan, Jelle Welagen, Stewart A. AndersonAbstract:GABAergic interneurons modulate cortical activity through the actions of distinct subgroups. Recent studies using interneuron transplants have shown tremendous promise as cell-based therapies for seizure disorders, Parkinson’s disease, and in the study of neocortical plasticity. Previous reports identified a spatial bias for the origins of parvalbumin (PV)- and somatostatin (SST)expressing interneuron subgroups within the medial Ganglionic Eminence (MGE). In the current study, the mitotic origins of these interneurons are examined by harvesting MGE cells at 2 time points and evaluating their neurochemical profiles after transplantation into neonatal mouse cortex. Although the dorsal MGE (dMGE)-SST and ventral MGE (vMGE)-PV bias were confirmed, both subgroups originate from progenitors located throughout the MGE. The dMGE bias was also found for SST subgroups that coexpress calretinin or reelin. In contrast, another major subgroup of SST interneuron, neuropeptide Y-expressing, does not appear to originate within the MGE. Finally, novel evidence is provided that a clinically important subtype of PV-expressing interneuron, the chandelier (axo-axonic) cell, is greatly enriched in transplants from the vMGE at embryonic day 15. These findings have important implications both for the study of interneuron fate determination and for studies that use interneuron precursor transplantation to alter cortical activity.
-
sonic hedgehog signaling confers ventral telencephalic progenitors with distinct cortical interneuron fates
Neuron, 2010Co-Authors: Qing Xu, Kenneth Campbell, Holly Moore, Ronald R Waclaw, Stewart A. AndersonAbstract:Summary Interneurons in the cerebral cortex regulate cortical functions through the actions of distinct subgroups that express parvalbumin, somatostatin, or calretinin. The genesis of the first two subgroups requires the expression of NKX2.1, which is maintained by SHH signaling during neurogenesis. In this paper, we report that mosaic elimination in the medial Ganglionic Eminence (MGE) of Smo , a key effector of SHH signaling, reveals that MGE progenitors retain a remarkable degree of plasticity during the neurogenic period. SHH signaling prevents the upregulation of GSX2 and conversion of some MGE progenitors to a caudal Ganglionic Eminence-like, bipolar calretinin-expressing cell fate that is promoted by GSX2. In addition, a higher level of SHH signaling promotes the generation of the somatostatin-expressing interneuron at the expense of parvalbumin-expressing subgroup. These results indicate that cortical interneuron diversity, a major determinant of cortical function, is critically influenced by differential levels of SHH signaling within the ventral telencephalon.
-
origins of cortical interneuron subtypes
The Journal of Neuroscience, 2004Co-Authors: Qing Xu, Estanislao De La Cruz, John L.r. Rubenstein, I Cobos, Stewart A. AndersonAbstract:Cerebral cortical functions are conducted by two general classes of neurons: glutamatergic projection neurons and GABAergic interneurons. Distinct interneuron subtypes serve distinct roles in modulating cortical activity and can be differentially affected in cortical diseases, but little is known about the mechanisms for generating their diversity. Recent evidence suggests that many cortical interneurons originate within the subcortical telencephalon and then migrate tangentially into the overlying cortex. To test the hypothesis that distinct interneuron subtypes are derived from distinct telencephalic subdivisions, we have used an in vitro assay to assess the developmental potential of subregions of the telencephalic proliferative zone (PZ) to give rise to neurochemically defined interneuron subgroups. PZ cells from GFP+ donor mouse embryos were transplanted onto neonatal cortical feeder cells and assessed for their ability to generate specific interneuron subtypes. Our results suggest that the parvalbumin- and the somatostatin-expressing interneuron subgroups originate primarily within the medial Ganglionic Eminence (MGE) of the subcortical telencephalon, whereas the calretinin-expressing interneurons appear to derive mainly from the caudal Ganglionic Eminence (CGE). These results are supported by findings from primary cultures of cortex from Nkx2.1 mutants, in which normal MGE fails to form but in which the CGE is less affected. In these cultures, parvalbumin- and somatostatin-expressing cells are absent, although calretinin-expressing interneurons are present. Interestingly, calretinin-expressing bipolar interneurons were nearly absent from cortical cultures of Dlx1/2 mutants. By establishing spatial differences in the origins of interneuron subtypes, these studies lay the groundwork for elucidating the molecular bases for their distinct differentiation pathways.
-
Origin and Molecular Specification of Striatal Interneurons
The Journal of Neuroscience, 2000Co-Authors: Oscar Marín, Stewart A. Anderson, John L.r. RubensteinAbstract:The striatum, the largest component of the basal ganglia, contains projection neurons and interneurons. Whereas there is considerable agreement that the lateral Ganglionic Eminence (LGE) is the origin of striatal projection neurons, less is known about the origin of striatal interneurons. Using focal injections of retrovirus into the ventral telencephalon in vitro , we demonstrate that most striatal interneurons tangentially migrate from the medial Ganglionic Eminence (MGE) or the adjacent preoptic/anterior entopeduncular areas (POa/AEP) and express the NKX2.1 homeodomain protein. Although the majority of striatal interneurons (cholinergic, calretinin + , and parvalbumin + ) maintain the expression of NKX2.1 into adulthood, most of the interneurons expressing somatostatin (SOM), neuropeptide Y (NPY), and neural nitric oxide synthase (NOS) appear to downregulate the expression of NKX2.1 as they exit the neuroepithelium. Analysis of striatal development in mice lacking Nkx2.1 suggests that this gene is required for the specification of nearly all striatal interneurons. Similar analysis of mice lacking the Mash1 basic helix–loop–helix (bHLH) or both the Dlx1 and Dlx2 homeodomain transcription factors demonstrates that these genes are required for the differentiation of striatal interneurons. Mash1 mutants primarily have a reduction in early-born striatal interneurons, whereas Dlx1/2 mutants primarily have reduced numbers of late-born striatal interneurons. We also present evidence implicating the Lhx6 and Lhx7 LIM-homeobox genes in the development of distinct interneuron subtypes. Finally, we hypothesize that, within the MGE, radially migrating cells generally become projection neurons, whereas tangentially migrating cells mainly form interneurons of the striatum and cerebral cortex.
Cecilia Eriksson - One of the best experts on this subject based on the ideXlab platform.
-
neuronal differentiation following transplantation of expanded mouse neurosphere cultures derived from different embryonic forebrain regions
Experimental Neurology, 2003Co-Authors: Cecilia Eriksson, Anders Bjorklund, Klas WictorinAbstract:In vitro, expanded neurospheres exhibit multipotent properties and can differentiate into neurons, astrocytes and oligodendrocytes. In vivo, cells from neurospheres derived from mouse fetal forebrain have previously been reported to predominantly differentiate into glial cells, and not into neurons. Here we isolated stem/progenitor cells from E13.5 lateral Ganglionic Eminence (LGE), medial Ganglionic Eminence (MGE) and cortical primordium, of a green fluorescent protein (GFP)-actin transgenic mouse. Free-floating neurospheres were expanded in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) and implanted after five to six passages into the striatum, hippocampus and cortex of neonatal rats. Cell suspensions of primary LGE tissue were prepared and grafted in parallel. Grafted cells derived from the primary tissue displayed widespread incorporation into all regions, as visualized with the mouse-specific antibody M2, or mouse satellite DNA in situ hybridization, and differentiated into both neurons, astrocytes and oligodendrocytes. Grafts of neurosphere cells derived from the LGE, MGE and cortical primordium differentiated primarily into astrocytes, but contained low but significant numbers of GFP-immunoreactive neurons. Neurons derived from LGE neurospheres were of three types: cells with the morphology of medium-sized densely spiny projection neurons in the striatum; cells with interneuron-like morphologies in striatum, cortex and hippocampus; and cells integrating into SVZ and migrating along the RMS to the olfactory bulb. MGE- or cortical primordium-derived neurospheres differentiated into interneuron-like cells in both striatum and hippocampus. The results demonstrate the ability of in vitro expanded neural stem/progenitor cells to generate both neurons and glia after transplantation into neonatal recipients, and differentiate in a region-specific manner into mature neurons with morphological features characteristic for each target site.
-
neuronal differentiation following transplantation of expanded mouse neurosphere cultures derived from different embryonic forebrain regions
Experimental Neurology, 2003Co-Authors: Cecilia Eriksson, Anders Bjorklund, Klas WictorinAbstract:In vitro, expanded neurospheres exhibit multipotent properties and can differentiate into neurons, astrocytes and oligodendrocytes. In vivo, cells from neurospheres derived from mouse fetal forebrain have previously been reported to predominantly differentiate into glial cells, and not into neurons. Here we isolated stem/progenitor cells from E13.5 lateral Ganglionic Eminence (LGE), medial Ganglionic Eminence (MGE) and cortical primordium, of a green fluorescent protein (GFP)-actin transgenic mouse. Free-floating neurospheres were expanded in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) and implanted after five to six passages into the striatum, hippocampus and cortex of neonatal rats. Cell suspensions of primary LGE tissue were prepared and grafted in parallel. Grafted cells derived from the primary tissue displayed widespread incorporation into all regions, as visualized with the mouse-specific antibody M2, or mouse satellite DNA in situ hybridization, and differentiated into both neurons, astrocytes and oligodendrocytes. Grafts of neurosphere cells derived from the LGE, MGE and cortical primordium differentiated primarily into astrocytes, but contained low but significant numbers of GFP-immunoreactive neurons. Neurons derived from LGE neurospheres were of three types: cells with the morphology of medium-sized densely spiny projection neurons in the striatum; cells with interneuron-like morphologies in striatum, cortex and hippocampus; and cells integrating into SVZ and migrating along the RMS to the olfactory bulb. MGE- or cortical primordium-derived neurospheres differentiated into interneuron-like cells in both striatum and hippocampus. The results demonstrate the ability of in vitro expanded neural stem/progenitor cells to generate both neurons and glia after transplantation into neonatal recipients, and differentiate in a region-specific manner into mature neurons with morphological features characteristic for each target site.
Gordon Fishell - One of the best experts on this subject based on the ideXlab platform.
-
satb1 is an activity modulated transcription factor required for the terminal differentiation and connectivity of medial Ganglionic Eminence derived cortical interneurons
The Journal of Neuroscience, 2012Co-Authors: Jennie L Close, Natalia V De Marco Garcia, Renata Batistabrito, Elsa Rossignol, Bernardo Rudy, Gordon FishellAbstract:Although previous work identified transcription factors crucial for the specification and migration of parvalbumin (PV)-expressing and somatostatin (SST)-expressing interneurons, the intrinsic factors required for the terminal differentiation, connectivity, and survival of these cell types remain uncharacterized. Here we demonstrate that, within subpopulations of cortical interneurons, Satb1 (special AT-rich binding protein) promotes terminal differentiation, connectivity, and survival in interneurons that express PV and SST. We find that conditional removal of Satb1 in mouse interneurons results in the loss of a majority of SST-expressing cells across all cortical layers, as well as some PV-expressing cells in layers IV and VI, by postnatal day 21. SST-expressing cells initially migrate to the cortex in Satb1 mutant mice, but receive reduced levels of afferent input and begin to die during the first postnatal week. Electrophysiological characterization indicates that loss of Satb1 function in interneurons results in a loss of functional inhibition of excitatory principal cells. These data suggest that Satb1 is required for medial Ganglionic Eminence-derived interneuron differentiation, connectivity, and survival.
-
gabaergic interneuron lineages selectively sort into specific cortical layers during early postnatal development
Cerebral Cortex, 2011Co-Authors: Goichi Miyoshi, Gordon FishellAbstract:It is of considerable interest to determine how diverse subtypes of γ-aminobutyric acidergic (GABAergic) interneurons integrate into the functional network of the cerebral cortex. Using inducible in vivo genetic fate mapping approaches, we found that interneuron precursors arising from the medial Ganglionic Eminence (MGE) and caudal Ganglionic Eminence (CGE) at E12.5, respectively, populate deep and superficial cortical layers in a complementary manner in the mature cortex. These age-matched populations initiate tangential migration into the cortex simultaneously, migrate above and below the cortical plate in a similar ratio, and complete their entrance into the cortical plate by P1. Surprisingly, while these 2 interneuron populations show a comparable layer distribution at P1, they subsequently segregate into distinct cortical layers. In addition, the initiation of the radial sorting within each lineage coincided well with the upregulation of the potassium/chloride cotransporter KCC2. Moreover, layer sorting of a later born (E16.5) CGE-derived population occurred with a similar time course to the earlier born E12.5 cohorts, further suggesting that this segregation step is controlled in a subtype specific manner. We conclude that radial sorting within the early postnatal cortex is a key mechanism by which the layer-specific integration of GABAergic interneurons into the emerging cortical network is achieved.
-
genetic fate mapping reveals that the caudal Ganglionic Eminence produces a large and diverse population of superficial cortical interneurons
The Journal of Neuroscience, 2010Co-Authors: Goichi Miyoshi, Robert P Machold, Vitor H Sousa, Theofanis Karayannis, Jens Hjerlingleffler, Simon J B Butt, James Battiste, Jane E Johnson, Gordon FishellAbstract:By combining an inducible genetic fate mapping strategy with electrophysiological analysis, we have systematically characterized the populations of cortical GABAergic interneurons that originate from the caudal Ganglionic Eminence (CGE). Interestingly, in comparison to medial Ganglionic Eminence (MGE)-derived cortical interneuron populations, the initiation (E12.5) and peak production (E16.5) of interneurons from this embryonic structure occurs three days later in development. Moreover, unlike either pyramidal cells or MGE-derived cortical interneurons, CGE-derived interneurons do not integrate into the cortex in an inside-out manner but preferentially (75%) occupy superficial cortical layers independent of birthdate. In contrast to previous estimates, CGE-derived interneurons are both considerably greater in number (around 30% of all cortical interneurons) and diversity (comprised by at least nine distinct subtypes). Furthermore, we have found that a large proportion of CGE-derived interneurons, including the neurogliaform subtype, express the glycoprotein Reelin. In fact, most CGE-derived cortical interneurons express either Reelin or vasoactive intestinal polypeptide (VIP). Thus, in conjunction with previous studies, we have now determined the spatial and temporal origins of the vast majority of cortical interneuron subtypes.
