ERK and PKA signaling drive the evolutionary expansion of the cortex
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ABSTRACT:
PROVIDER: PRJNA1243344 | ENA |
REPOSITORIES: ENA
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Project description:The signaling pathways governing cortical neurogenesis and gliogenesis in mice are well-defined, yet how they integrate to control the lineage progression of cortical radial glia (RGs) remains incompletely understood. Here, using mouse genetic models, it is demonstrated that ERK and PKA signaling cooperate to preserve the neurogenic capacity of cortical RGs by suppressing the gliogenic pathways YAP/TAZ and SHH. Specifically, YAP/TAZ signaling drives cortical RGs toward an ependymal fate, while SHH signaling promotes the generation of tripotential intermediate progenitor cells that produce cortical astrocytes and oligodendrocytes, and olfactory bulb interneurons. Reanalysis of published human cortical scRNA-seq data further revealed that the functional roles of these signaling pathways are conserved between mouse and human cortical RGs. Furthermore, human cortical outer RGs acquire dominant ERK/PKA signaling through a self-reinforcing loop that suppresses both YAP and SHH signaling, markedly enhancing self-renewal and extending neurogenesis. Thus, a tripartite network of ERK/PKA, YAP/TAZ, and SHH whose cross-repressive logic coordinates neurogenesis with gliogenesis and may underlie evolutionary expansion, providing a framework for understanding cortical development and evolution, is identified.
2025-07-01 | GSE293205 | GEO
Project description:Human exceptional cognition stems from evolutionarily derived cortical adaptations that drive expansive neurogenesis. Deciphering these mechanisms is crucial for understanding mammalian cortical evolution. In this study, we employ the ferret model to comprehensively map molecular profiles and lineage dynamics of cortical radial glia (RGs). By applying scRNA-Seq to ferret and human cortices, we identify conserved regulatory programs underlying cortical neurogenesis and gliogenesis in mammals. Through integrated scRNA-Seq, BrdU pulse-chase labeling, and immunohistochemical approaches, we demonstrate that, similar to their human counterparts, ferret cortical outer radial glia (oRGs), exhibit enhanced ERK and PKA signaling. ERK and PKA act in a mutually reinforcing manner to boost oRG self-renewal and neurogenesis, while inhibiting gliogenesis and prolonging the neurogenic period. Furthermore, we identify regional specialization within cortical gliogenic RGs: YAP/TAZ activation drives ventricular zone truncated radial glia (tRGs) toward ependymal fate in medial cortex, whereas SHH signaling instructs lateral cortical tRGs to generate tripotential intermediate progenitor cells, which serve as a shared source of astrocytes, oligodendrocytes, and olfactory bulb interneurons. Our data support a model in which mammalian cortical neurogenesis, gliogenesis, and evolutionary expansion are co-regulated through an integrated signaling network involving ERK, PKA, YAP/TAZ, and SHH. These findings provide key insights into the molecular and cellular mechanisms driving cortical development and evolution.
2025-08-07 | GSE304846 | GEO
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| S-EPMC12850263 | biostudies-literature
Project description:As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia. Despite their evolutionary relevance, the genomic changes driving human basal radial glia biology remain uncharacterized. We used comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans. Focusing specifically on basal radial glia, we discovered that morphoregulatory enhancer activity and gene expression signatures distinguish human basal radial glia from other great apes. Functional analysis of the morphoregulatory genes FAM107A and CNGA3 in human organoids revealed that these genes contribute to the morphological complexity of human basal radial glia. Taken together, our inter-species comparison of basal radial glia suggests that human-specific morphoregulatory signatures characterise neocortex evolution.
2026-08-04 | GSE331434 | GEO
Project description:As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia. Despite their evolutionary relevance, the genomic changes driving human basal radial glia biology remain uncharacterized. We used comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans. Focusing specifically on basal radial glia, we discovered that morphoregulatory enhancer activity and gene expression signatures distinguish human basal radial glia from other great apes. Functional analysis of the morphoregulatory genes FAM107A and CNGA3 in human organoids revealed that these genes contribute to the morphological complexity of human basal radial glia. Taken together, our inter-species comparison of basal radial glia suggests that human-specific morphoregulatory signatures characterise neocortex evolution.
2026-08-04 | GSE331437 | GEO
Project description:As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia. Despite their evolutionary relevance, the genomic changes driving human basal radial glia biology remain uncharacterized. We used comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans. Focusing specifically on basal radial glia, we discovered that morphoregulatory enhancer activity and gene expression signatures distinguish human basal radial glia from other great apes. Functional analysis of the morphoregulatory genes FAM107A and CNGA3 in human organoids revealed that these genes contribute to the morphological complexity of human basal radial glia. Taken together, our inter-species comparison of basal radial glia suggests that human-specific morphoregulatory signatures characterise neocortex evolution.
2026-08-04 | GSE331436 | GEO
Project description:As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia. Despite their evolutionary relevance, the genomic changes driving human basal radial glia biology remain uncharacterized. We used comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans. Focusing specifically on basal radial glia, we discovered that morphoregulatory enhancer activity and gene expression signatures distinguish human basal radial glia from other great apes. Functional analysis of the morphoregulatory genes FAM107A and CNGA3 in human organoids revealed that these genes contribute to the morphological complexity of human basal radial glia. Taken together, our inter-species comparison of basal radial glia suggests that human-specific morphoregulatory signatures characterise neocortex evolution.
2026-08-04 | GSE331435 | GEO
Project description:Since the discovery of radial glia as the source of neurons, their heterogeneity in regard to neurogenesis has been described by clonal and time-lapse analysis in vitro. However, the molecular determinants specifying neurogenic radial glia differently from radial glia that mostly self-renew remain ill-defined. Here, we isolated two radial glial subsets that co-exist at mid-neurogenesis in the developing cerebral cortex and their immediate progeny. While one subset generates neurons directly, the other is largely non-neurogenic but also gives rise to Tbr2-positive basal precursors, thereby contributing indirectly to neurogenesis. Isolation of ; these distinct radial glia subtypes allowed determining interesting differences in their transcriptome. These transcriptomes were also strikingly different from the transcriptome of radial glia isolated at the end of neurogenesis. This analysis therefore identifies, for the first time, the lineage origin of basal progenitors and the molecular differences of this lineage in comparison to directly neurogenic and gliogenic radial glia. Experiment Overall Design: Comparison of radial glial subtypes
2008-06-18 | E-GEOD-8034 | biostudies-arrayexpress
Project description:Neural cell type diversity arises from both spatial and temporal patterning of neural stem cells. Although spatial patterning mechanisms have been extensively studied, temporal patterning mechanisms remain relatively unexplored. In this study, we addressed generation of diverse neural cell types through lineage progression of mouse cortical radial glia. The time series scRNA-seq and snATAC-seq of mouse cortical development revealed that radial glia temporally transitioned from neurogenesis to gliogenesis. During gliogenic stages, various cell types were generated simultaneously along multidirectional lineage trajectories. We established comprehensive molecular maps for cortical lineage commitment and cellular diversification. The transcriptome and epigenome of cortical radial glia exhibit temporal dynamics, as revealed by scRNA-seq and snATAC-seq. Lhx2, a transcription factor with temporal dynamic chromatin binding activities, was identified as a key regulator of the neurogenesis-to-gliogenesis transition. It maintains neurogenic competence by establishing the active epigenetic state of its target genes.
2024-09-03 | GSE276209 | GEO
Project description:Neural cell type diversity arises from both spatial and temporal patterning of neural stem cells. Although spatial patterning mechanisms have been extensively studied, temporal patterning mechanisms remain relatively unexplored. In this study, we addressed generation of diverse neural cell types through lineage progression of mouse cortical radial glia. The time series scRNA-seq and snATAC-seq of mouse cortical development revealed that radial glia temporally transitioned from neurogenesis to gliogenesis. During gliogenic stages, various cell types were generated simultaneously along multidirectional lineage trajectories. We established comprehensive molecular maps for cortical lineage commitment and cellular diversification. The transcriptome and epigenome of cortical radial glia exhibit temporal dynamics, as revealed by scRNA-seq and snATAC-seq. Lhx2, a transcription factor with temporal dynamic chromatin binding activities, was identified as a key regulator of the neurogenesis-to-gliogenesis transition. It maintains neurogenic competence by establishing the active epigenetic state of its target genes.
2025-06-05 | GSE298892 | GEO