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 cerebral cortex, the anatomical foundation of human intelligence, underpins our advanced cognition and language. Deciphering the regulatory mechanisms driving its remarkable expansion is essential for unraveling the unique features that define the human brain and species. Here, we demonstrate that ERK and PKA signaling pathways coordinately maintain the neurogenic identity and lineage specification of cortical radial glia (RGs) by suppressing YAP and SHH signaling. Conversely, YAP signaling promotes the RG-ependymal glial cell lineage by inhibiting ERK, PKA, and SHH signaling, while SHH signaling facilitates the generation of cortical tripotential intermediate progenitor cells (Tri-IPCs) from RG by repressing ERK, PKA, and YAP signaling. Cortical Tri-IPCs exhibit a sequential differentiation potential, giving rise to cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons. Importantly, we provide compelling evidence for the evolutionary conservation of these molecular mechanisms between mice and humans. Thus, ERK and PKA signaling in cortical RG establish a mutually reinforcing positive feedback loop, mediated through repressing gliogenic YAP and SHH signaling, which collectively promote human cortical expansion. This study identifies a unifying principle governing mammalian cortical neurogenesis, gliogenesis, expansion, and evolution.
2025-07-01 | GSE293205 | GEO
Project description:Human serpina3 modulates cortex expansion and folding
| PRJNA694137 | ENA
Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals. We performed gene expression microarray analysis on embryonic mouse cerebral cortex derived from Trnp1 knockdown and control animals.
2013-04-26 | E-GEOD-40582 | biostudies-arrayexpress
Project description:The molecular basis for cortical expansion during evolution remains largely unknown. Here, we report that fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signaling promotes the self-renewal and expansion of cortical radial glial (RG) cells. Furthermore, FGF-ERK signaling induces bone morphogenic protein 7 (Bmp7) expression in cortical RG cells, which increases the length of the neurogenic period. We demonstrate that ERK signaling and Sonic Hedgehog (SHH) signaling mutually inhibit each other in cortical RG cells. We provide evidence that ERK signaling is elevated in cortical RG cells during development and evolution. We propose that the expansion of the mammalian cortex, notably in human, is driven by the ERK-BMP7-GLI3R signaling pathway in cortical RG cells, which participates in a positive feedback loop through antagonizing SHH signaling. We also propose that the relatively short cortical neurogenic period in mice is partly due to mouse cortical RG cells receiving higher SHH signaling that antagonizes ERK signaling.
2023-08-09 | GSE240381 | GEO
Project description:Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer whose biology is still poorly understood. Using a multiplexed inhibitor beads assay, we identified active kinases in SCLC. Among those, we found that PKA is critical for the expansion of SCLC in culture and in vivo. PKA promotes the neuroendocrine epithelial state associated with SCLC tumor-initiating cells. Phosphoproteomics analyses identify ~200 PKA substrates and show that PKA controls multiple facets of SCLC growth. Notably, the PP2A phosphatase counteracts the oncogenic effects of PKA, and PP2A activators inhibit SCLC as single agents and with chemotherapy. Our data uncover key signaling networks in SCLC and indicate that targeting the PKA/PP2A pathway may help inhibit this lethal neuroendocrine cancer.
2020-02-11 | GSE126353 | GEO
Project description:Folding of the mammalian cerebral cortex into sulcal fissures and gyral peaks is the result of complex processes that are incompletely understood. Previously we showed that genetic deletion of Flrt1/3 adhesion molecules causes folding of the smooth mouse cortex into sulci resulting from increased lateral dispersion and faster neuron migration, without progenitor expansion. Here, we find that combining the Flrt1/3 double knockout with an additional genetic deletion that causes progenitor expansion, greatly enhances cortex folding. Expansion of intermediate progenitors by deletion of Cep83 results in enhanced formation of sulci. Expansion of apical progenitors by deletion of Fgf10 results in enhanced formation of gyri. Single cell transcriptomics and simulations suggest that changes in adhesive properties of cortical neurons, their proportions and densities in the cortical plate, combined with lateral dispersion during their radial migration are important folding parameters. These results identify key developmental mechanisms that cooperate to promote cortical gyrification
2025-05-20 | GSE267391 | GEO
Project description:Evolution of the mammalian brain encompassed a remarkable increase in size of cerebral cortex, including tangential and radial expansion, but the mechanisms underlying these key parameters are still largely unknown. Here, we identified the novel DNA associated protein TRNP1 as a regulator of cerebral cortical expansion in both these dimensions. Gain and loss of function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion, while lower levels promote radial expansion resulting in a potent increase in the generation of intermediate progenitors and outer radial glial cells resulting in folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences also in the cerebral cortex of human fetuses anticipating radial or tangential expansion respectively. Thus, the dynamic regulation of TRNP1 is critical to regulate tangential and radial expansion of the cerebral cortex in mammals.
2013-04-26 | GSE40582 | GEO
Project description:When exploring the role of Gαs and β-arrestin in nuclear transcriptional programs downstream from β2-adrenergic receptor (β2AR), we noticed a dearth of information on PKA-regulated genes sets. Thus, we first used the tetracycline-regulated expression of wild type PKA Cα subunit in HEK293 cells to develop a PKA signature. This approach revealed multiple PKA-regulated genes, including well known PKA downstream transcriptional targets, such as PCK1 and FOS, and many new PKA transcriptional targets whose underlying mechanism can now be explored.
2023-10-21 | GSE245789 | GEO
Project description:Cortex Folding by Combined Progenitor Expansion and Adhesion-Controlled Neuronal Migration
| PRJNA1111399 | ENA
Project description:Temperature preference behavior in Drosophila depends on the level of PKA signaling in the mushroom bodies. To identify new components downstream to PKA, we carried out a genome-wide screen for genes regulated by PKA signaling in the mushroom bodies. Using the Gal4-UAS system, we increased or decreased PKA activity in the mushroom bodies by expressing dominant-negative (UAS-PKADN) or constitutively active PKA (UAS-PKACA), respectively. Expression of PKA transgenes was targeted to the mushroom bodies using the mushroom body-specific MB247-Gal4 driver. PKA expression was induced for 12-16 hours in three-day-old adults by inactivating the temperature-sensitive Gal80 at the restrictive temperature. We then analyzed gene-expression profiles to identify the genes showing altered expression levels in response to the high or low PKA activity.
2014-03-25 | E-GEOD-28181 | biostudies-arrayexpress