Medial Ganglionic Eminence and Cortical Organoids Model Human Brain Development and Interneuron Migration
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97882 | GEO | 2017/07/21
SECONDARY ACCESSION(S): PRJNA383130
REPOSITORIES: GEO
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Project description:Organoid techniques provide unique platforms to model brain development and neurological disorders. While organoids recapitulating corticogenesis were established, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, remains to be developed. Here, we describe a system to generate MGE or cortex-specific organoids from human pluripotent stem cells. These organoids recapitulate the developments of MGE and cortex domains respectively. Population and single-cell transcriptomic profiling revealed transcriptional dynamics and lineage productions during MGE and cortical organoids development. Chromatin accessibility landscapes were found to be involved in this process. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, we applied fusion organoids as a model to investigate human interneuron migration. Together, our study provides a new platform for generating domain-specific brain organoids, for modeling human interneuron migration, and offers deeper insight into molecular dynamics during human brain development.
2017-07-21 | GSE98201 | GEO
Project description:Organoid techniques provide unique platforms to model brain development and neurological disorders. While organoids recapitulating corticogenesis were established, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, remains to be developed. Here, we describe a system to generate MGE or cortex-specific organoids from human pluripotent stem cells. These organoids recapitulate the developments of MGE and cortex domains respectively. Population and single-cell transcriptomic profiling revealed transcriptional dynamics and lineage productions during MGE and cortical organoids development. Chromatin accessibility landscapes were found to be involved in this process. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, we applied fusion organoids as a model to investigate human interneuron migration. Together, our study provides a new platform for generating domain-specific brain organoids, for modeling human interneuron migration, and offers deeper insight into molecular dynamics during human brain development.
2017-07-21 | GSE97881 | GEO
Project description:Organoid techniques provide unique platforms to model brain development and neurological disorders. While organoids recapitulating corticogenesis were established, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, remains to be developed. Here, we describe a system to generate MGE or cortex-specific organoids from human pluripotent stem cells. These organoids recapitulate the developments of MGE and cortex domains respectively. Population and single-cell transcriptomic profiling revealed transcriptional dynamics and lineage productions during MGE and cortical organoids development. Chromatin accessibility landscapes were found to be involved in this process. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, we applied fusion organoids as a model to investigate human interneuron migration. Together, our study provides a new platform for generating domain-specific brain organoids, for modeling human interneuron migration, and offers deeper insight into molecular dynamics during human brain development.
2017-07-21 | GSE97880 | GEO
Project description:Immature neurons generated by the subpallial MGE tangentially migrate to the cortex where they become parvalbumin-expressing (PV+) and somatostatin (SST+) interneurons. Here, we show that the Sp9 transcription factor controls the development of MGE-derived cortical interneurons. SP9 is expressed in the MGE subventricular zone and in MGE-derived migrating interneurons. Sp9 null and conditional mutant mice have approximately 50% reduction of MGE-derived cortical interneurons, an ectopic aggregation of MGE-derived neurons in the embryonic ventral telencephalon, and an increased ratio of SST+/PV+ cortical interneurons. RNA-Seq and SP9 ChIP-Seq reveal that SP9 regulates MGE-derived cortical interneuron development through controlling the expression of key transcription factors Arx, Lhx6, Lhx8, Nkx2-1, and Zeb2 involved in interneuron development, as well as genes implicated in regulating interneuron migration Ackr3, Epha3, and St18. Thus, Sp9 has a central transcriptional role in MGE-derived cortical interneuron development.
| S-EPMC6519701 | biostudies-literature
Project description:Medial Ganglionic Eminence and Cortical Organoids Model Human Brain Development and Interneuron Migration
| PRJNA383130 | ENA
Project description:In the mammalian cortex, about 60% of GABAergic interneurons, mainly including parvalbumin-expressing (PV+) and somatostatin (SST+) interneurons are generated from the medial ganglionic eminence (MGE) in the subpallium and tangentially migrate to the cortex. Here we analyze the role of the Sp9 transcription factor in regulating the development of MGE-derived cortical interneurons. We show that SP9 is widely expressed in the MGE subventricular zone (SVZ) and in MGE-derived migrating interneurons. By analyzing Sp9 null and conditional mutant mice, we demonstrate that Sp9 promotes MGE progenitor proliferation in the SVZ and is required for the normal patterning of tangential migration and the laminar distribution of MGE-derived cortical GABAergic interneurons. Loss of Sp9 function results in a ~50% reduction of MGE-derived cortical interneurons, an ectopic aggregation of MGE-derived neurons in the embryonic ventral telencephalon, and an increased ratio of SST+/PV+ cortical interneurons. Finally, we provide evidence that Sp9 regulates MGE derived cortical interneuron development through promoting expression of the Lhx6 and Lhx8 transcription factors.
2017-05-19 | GSE99049 | GEO
Project description:Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6, and Dlx2 expression, in vitro differentiation into neurons expressing GABA, and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies.SIGNIFICANCE STATEMENT Here we demonstrate that porcine medial ganglionic eminence, like rodents, exhibit a distinct transcriptional and interneuron-specific antibody profile, in vitro migratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic interneuron origins in the pig; and because a rich neurodevelopmental literature on embryonic mouse medial ganglionic eminence exists (with some additional characterizations in other species, e.g., monkey and human), our work allows direct neurodevelopmental comparisons with this literature.
| S-EPMC8026360 | biostudies-literature
Project description:Cortical interneurons arise from the ganglionic eminences in the ventral telencephalon and migrate tangentially to the cortex. Although RhoA and Cdc42, members of the Rho family of small GTPases, have been implicated in regulating neuronal migration, their respective roles in the tangential migration of cortical interneurons remain unknown. Here we show that loss of RhoA and Cdc42 in the ventricular zone (VZ) of the medial ganglionic eminence (MGE) using Olig2-Cre mice causes moderate or severe defects in the migration of cortical interneurons, respectively. Furthermore, RhoA- or Cdc42-deleted MGE cells exhibit impaired migration in vitro. To determine whether RhoA and Cdc42 directly regulate the motility of cortical interneurons during migration, we deleted RhoA and Cdc42 in the subventricular zone (SVZ), where more fate-restricted progenitors are located within the ganglionic eminences, using Dlx5/6-Cre-ires-EGFP (Dlx5/6-CIE) mice. Deletion of either gene within the SVZ does not cause any obvious defects in cortical interneuron migration, indicating that cell motility is not dependent upon RhoA or Cdc42. These findings provide genetic evidence that RhoA and Cdc42 are required in progenitors of the MGE in the VZ, but not the SVZ, for proper cortical interneuron migration.
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Project description: Not available
| S-EPMC8783944 | biostudies-literature
Project description:Although it is well established that the ventral telencephalon is the primary source of GABAergic cortical interneurons in rodents, little is known about the specification of specific interneuron subtypes. It is also unclear whether the potential to achieve a given fate is established at their place of origin or by signals received during their migration to or during their maturation within the cerebral cortex. Using both in vivo and in vitro transplantation techniques, we find that two major interneuron subgroups have largely distinct origins within the MGE. Somatostatin (SST)-expressing interneurons are primarily generated within the dorsal MGE, while parvalbumin (PV)-expressing interneurons primarily originate from the ventral MGE. In addition, we show that significant heterogeneity exists between gene expression patterns in the dorsal and ventral MGE. These results suggest that, like the spinal cord, neuronal fate determination in the ventral telencephalon is largely the result of spatially segregated, molecularly distinct microdomains arranged on the dorsal-ventral axis.
| S-EPMC2727678 | biostudies-literature