Rostrocaudal Areal Patterning of Human PSC-Derived Cortical Neurons by FGF8 Signaling
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PROVIDER: PRJNA435939 | ENA |
REPOSITORIES: ENA
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Project description:The cerebral cortex is subdivided into distinct areas that have particular functions. The rostrocaudal (R-C) gradient of fibroblast growth factor 8 (FGF8) signaling defines this areal identity during neural development. In this study, we recapitulated cortical R-C patterning in human pluripotent stem cell (PSC) cultures. Modulation of FGF8 signaling appropriately regulated the R-C markers, and the patterns of global gene expression resembled those of the corresponding areas of in vivo human fetal brains. Furthermore, we demonstrated the utility of this culture system in modeling the area-specific forebrain phenotypes (presumptive upper motor neuron (UMN) phenotypes) of amyotrophic lateral sclerosis (ALS). We anticipate that our culture system will contribute to studies of human neurodevelopment and neurological disease modeling.
2018-02-27 | GSE111106 | GEO
Project description: Not available
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Project description:Current organoid protocols are widely used to mechanistically study cortical development, evolution and brain pathologies. While these systems generate all major cortical cell types in histologically distinct compartments, they lack cortical area topography, which is initiated by gradients of signaling molecules released by signaling organizers that establish transcriptionally distinct domains along the rostro-caudal axis of the developing cortex. Here, we engineer human cortical assembloids that combine an organizer-like structure expressing FGF8 with an elongated organoid design to enable the controlled modulation of FGF8 signaling along the longitudinal organoid axis. We demonstrate that individual polarized cortical assembloids (polCA) mount a position-dependent transcriptional program that matches the in vivo rostro-caudal gene expression patterns. Importantly, positional identity is lost in polCA carrying a mutation in the FGFR3 gene associated with temporal lobe malformations and intellectual disability in humans. Similar to in vivo, this program is accompanied by transcriptional divergence of radial glia cells and excitatory neurons and their segregation along the longitudinal axis of individual organoids. Thus, this method reproduces in vivo cortical topography in individual organoids and enables the analysis of area-related phenotypes underlying human disorders.
2024-05-03 | GSE231319 | GEO
Project description:Current organoid protocols are widely used to mechanistically study cortical development, evolution and brain pathologies. While these systems generate all major cortical cell types in histologically distinct compartments, they lack cortical area topography, which is initiated by gradients of signaling molecules released by signaling organizers that establish transcriptionally distinct domains along the rostro-caudal axis of the developing cortex. Here, we engineer human cortical assembloids that combine an organizer-like structure expressing FGF8 with an elongated organoid design to enable the controlled modulation of FGF8 signaling along the longitudinal organoid axis. We demonstrate that individual polarized cortical assembloids (polCA) mount a position-dependent transcriptional program that matches the in vivo rostro-caudal gene expression patterns. Importantly, positional identity is lost in polCA carrying a mutation in the FGFR3 gene associated with temporal lobe malformations and intellectual disability in humans. Similar to in vivo, this program is accompanied by transcriptional divergence of radial glia cells and excitatory neurons and their segregation along the longitudinal axis of individual organoids. Thus, this method reproduces in vivo cortical topography in individual organoids and enables the analysis of area-related phenotypes underlying human disorders.
2024-05-03 | GSE231318 | GEO
Project description:To map enhancers involved in regional patterning of cortical progenitors, we performed TF ChIP for patterning transcription factors as well as assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach identified a cortical Regionalization TF network and VZ enhancers involved in cortical regional patterning.
2021-09-07 | GSE183130 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE24440: Sprouting transcriptome in cortical neurons: young GSE24441: Sprouting transcriptome in cortical neurons: aged Refer to individual Series
2010-11-15 | E-GEOD-24442 | biostudies-arrayexpress
Project description:The establishment of the fronto-temporal axis in the developing human cortex is achieved by temporary signaling activity coming from secondary organizers. However, studying this process remains challenging due to the limited access to fetal material and inaccuracy of animal models in mimicking human-specific aspects. Although human brain organoids provide a potential solution to study this, their lack of axial organization does not supply the appropriate positional information needed to recapitulate detailed patterning processes in situ. Here, we develop a method that combines a cell line expressing the morphogen FGF8 fused to organoids engineered with PDMS moulds representing the exact length of the developing brain, resulting in the formation of polarized cortical organoids, or PolarOids. Thanks to a dose-sensitive reporter for anterior cortical differentiation, we carefully titrate and time the fusion dynamics to elicit a gradient in the patterned tissue while preserving neural activity as assessed through electrophysiology. We show that our localized FGF8 source is sufficient to trigger a distance-dependent transcriptional signature that matches fronto-temporal cortical fates in vivo. Lastly, we use these PolarOids to model a disease-relevant FGFR3 mutation and describe the transcriptional loss of axial gradient formation underlying a dramatic cortical phenotype observed in patients. As such, Polaroids provide a powerful tool to model hitherto neglected human diseases caused by defects in antero-posterior patterning in the brain
2024-05-03 | GSE175592 | GEO
Project description:Gene expression from icas9 human iPSC derived cortical neurons treated with and without doxycycline
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Project description:E18 embryonic rat cortical neurons cultured in vitro are infected with lentivirus expressing control or PHF6shRNA-2, and harvested 5 days after infection pLL3.7 lentivirus expressing control or PHF6shRNA-2 was generated in 293T cells and concentrated using ultracentrifuge. In vitro cultured cortical neurons were infected and RNA was harvested 5 days after infection. PHF6 knockdown was validated by QPCR before sample was processed for microarray analysis.
2013-08-01 | E-GEOD-45953 | biostudies-arrayexpress
Project description:This data would help in understanding the effect of FGF8 in the development of neurons critical for human puberty (GnRH neurons)
2022-07-20 | E-MTAB-11767 | biostudies-arrayexpress