A conserved logic for the development of cortical layering in tetrapods [St_30-53]
Ontology highlight
ABSTRACT:
ORGANISM(S): Pleurodeles waltl
PROVIDER: GSE308588 | GEO | 2026/04/22
REPOSITORIES: GEO
Similar Datasets
Project description:The evolutionary origin of the cerebral cortex, a brain region classically defined by the presence of neuronal layers, remains elusive. We find that the salamander dorsal pallium is layered: superficial and deep-layer neurons have distinct birthdates, transcriptomic identities and projections. Using lineage tracing and scRNA-seq, we uncover evolutionarily-conserved principles of cortical development, including temporal patterning in multipotent radial glia progenitors, and the deployment of intermediate progenitor cells. We also describe the transcriptomic divergence of neuronal differentiation programs across species, suggesting that evolutionary diversification of cortical neuron types stems from changes in gene regulation after cell cycle exit. Our findings challenge long-held assumptions on the development and evolution of the cerebral cortex, and suggest that the mammalian neocortex evolved through modifications of a conserved developmental framework.
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Project description:The cerebral cortex shows species-specific variations in size and organization, likely accounting for distinct behavioral abilities. These structural differences may reflect evolutionary changes in the developmental expression of shared genes. To investigate this possibility, we used machine vision to identify and compare cell-type-specific gene expression patterns in the developing mouse and human neocortex, and in human cortical organoids. This identified genes with evolutionary conserved/divergent transcriptional regulation, revealing species-specific cyto-temporal gene expression patterns. Among such genes, the transcription factor JUNB showed mutually exclusive expression in human progenitors and mouse neurons. Through cell-type-specific gain- and loss-of-function experiments in mice and human organoids, we show that JUNB bidirectionally controls human cortical features, including progenitor proliferation rates, neuronal production timing, and total neuronal output. We identify IRF1 as a human RG-specific regulator that, when expressed in mouse RG, activates JUNB and recruits human-like gene regulatory networks, demonstrating cross-species activation of poised developmental programs. Together, these findings reveal how cyto-temporal regulation of shared genes drives species-specific cortical features and provides a molecular framework to understand and manipulate these evolutionary programs.
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Project description:The layered structure of the cerebral cortex is formed through a complicated sequence of highly controlled stages. During this process, the perturbations of neuronal migration and cell division can result in a rare disorder called cortical heterotopia. Heterotopia patients can have recurrent epileptic seizures, developmental delays, and mild intellectual disabilities. Studying heterotopia has been challenging because human mutations linked to the disease often do not result in heterotopia formation in mouse models. EML1 is a microtubule-binding protein, and it stands out as the first heterotopia-associated gene where mutations lead to heterotopia formation in both humans and mice. In this study, we conducted a comparative proteomic analysis of the Eml1 cKO heterotopic mice cortices and neuronal progenitor primary cells during cerebral cortex development. We performed label-free and dimethyl labeling-based quantitative proteomic approaches, and microtubule pelleting assays to understand how Eml1 depletion disrupts protein networks in cortical tissue and neuronal progenitor primary cells during cerebral cortex development.
2025-07-07 | PXD052486 | Pride
Project description:The coordination of progenitor self-renewal, neuronal production and migration is essential to the normal development and evolution of the cerebral cortex. Numerous studies have shown that the Notch, Wnt/beta-catenin and Neurogenin pathways contribute separately to progenitor expansion, neurogenesis, and neuronal migration, but it is unknown how these signals are coordinated. In vitro studies suggested that the mastermind-like 1 (MAML1) gene, homologue of the Drosophila Mastermind, plays a role in coordinating the afore-mentioned signaling pathways, yet its role during cortical development remains largely unknown. Here we show that ectopic expression of dominant-negative MAML (dnMAML) causes exuberant neuronal production in the mouse cortex without disrupting neuronal migration. Comparing the transcriptional consequences of dnMAML and Neurog2 ectopic expression revealed a complex genetic network controlling the balance of progenitor expansion versus neuronal production. Manilpulation of MAML and Neurog2 in cultured human cerebral stem cells exposed interactions with the same set of signaling pathways. Thus, our data suggest that evolutionary changes that affect the timing, tempo and density of successive neuronal layers of the small lissencephalic rodent and large convoluted primate cerebral cortex depend on similar molecular mechanisms that act from the earliest developmental stages.
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Project description:Multiple sclerosis (MS) affects the cerebral cortex, inducing cortical atrophy and neuronal and synaptic pathology. Despite the fact that women are more susceptible to getting MS, men with MS have worse disability progression. Here, we address sex differences in neurodegenerative mechanisms focusing on the cerebral cortex using the MS model, chronic experimental autoimmune encephalomyelitis (EAE). RNA sequencing of neurons in cerebral cortex during EAE showed robust differential gene expression in male EAE mice compared to male healthy, age-matched, control mice. In contrast, there were few differences in female EAE mice compared to female controls. The most enriched differential gene expression pathways in male mice during EAE were mitochondrial dysfunction and oxidative phosphorylation. Mitochondrial morphology showed significant abnormalities in the cerebral cortex of EAE males, but not EAE females. Regarding function, synaptosomes isolated from cerebral cortex of male EAE mice demonstrated decreased oxygen consumption rates during respirometry assays. Together, cortical neuronal transcriptomics, mitochondrial morphology, and functional respirometry assays in synaptosomes revealed worse neurodegeneration in male EAE mice. This is consistent with worse neurodegeneration in MS men and reveals a model and a target to develop treatments to prevent cortical neurodegeneration and mitigate disability progression in MS men.
2023-11-13 | GSE239455 | GEO
Project description:<p>Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. It is known that epilepsy, specific learning deficits and intellectual disability, cerebral palsy, and abnormalities of brain volume can be attributed in many cases to pathological malformations of the cerebral cortex. Although these consequences, such as epilepsy and intellectual disability, might appear broadly in the population as due to complex traits, this study's focus on those associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Research has thus far uncovered dozens of genes responsible for these conditions and dissected the mechanisms underlying early cortical development in animals. However, this progress represents only the dawn of understanding the complex genetic network and neuronal architecture of the uniquely human cerebral cortex.</p> <p>The overall goal of this study is to define the genetic bases of human cerebral cortical development. This is accomplished through (1) the ascertainment of families with disorders of human brain development and malformation, (2) categorizing these using medical, physical and neuroimaging data, and (3) mapping and identifying the gene causing the disorder of cortical development, which can then be investigated for its normal expression and function, and role in human disease. </p>
| phs000492 | dbGaP
Project description:All animals have specialized brain structures with a neuronal composition optimized for their survival and adaptation. The mammals share the laminar structure of the cerebral cortex, where a certain repertoire of excitatory neuron subtypes is arranged in specific tangential layers. However, the quantitative balance of subtypes is highly specialized in each species due to unknown developmental mechanisms. It is of particular interest to understand how the relatively conserved process of mammalian corticogenesis is modified in each species to achieve an optimized neuronal composition. Here, we show that fine-tuning the temporal progression of neurogenesis is the critical mechanism of the species-specific neuronal repertoire through our comparative study of mouse and rat cortical excitatory neurogenesis. Clonal tracing of individual progenitors revealed that rats produce more deep layer (DL) subtypes than mice, but both species produce essentially the same number of upper layer (UL) neurons. Such subtype-specific dosage optimization is mediated by the selective expansion of the early neurogenetic window for DL production in rats, as revealed by our neuronal birthdating and single cell transcriptomics. We found that the temporal neurogenetic status of the progenitors is encoded, at least in part, by Ccnd1 expression, as evidenced by the precocious UL production upon Ccnd1 knockdown in the rat mid-neurogenetic phase, when significant expression is maintained at levels comparable to the earlier phase in mice. Collectively, these results suggest that the closely related rodents, mouse and rat, construct their cortical structure with specific neuronal composition through the pinpointed specialization in developmental progression while maintaining the basic framework of the inside-out sequence of cortical excitatory neurogenesis. This study used mice and rats, the most common laboratory mammals with a close evolutionary relationship, to reveal the detailed molecular and cellular mechanisms behind the fine-tuning of cell composition in the cerebral cortex. Such a detailed comparison dissected the specialized and unchanged processes of corticogenesis during the evolutionary divergence of the two species. This further provides insights into the evolvability and developmental constraints of mammalian corticogenesis.
2025-01-21 | GSE287210 | GEO
Project description:A conserved logic for the development of cortical layering in tetrapods [St_30-53]
| PRJNA1331652 | ENA
Project description:Neuroserpin is a serine protease inhibitor that regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin is strongly expressed during nervous system development as well as during adulthood, when it is predominantly found in regions eliciting synaptic plasticity. In the hippocampus, neuroserpin regulates developmental neurogenesis, synaptic maturation and in adult mice it modulates synaptic plasticity and controls cognitive and social behavior. High expression levels of neuroserpin in the cerebral cortex starting from prenatal stage and persisting during adulthood suggest an important role for the serpin in the formation of this brain region and in the maintenance of cortical functions. In order to uncover neuroserpin function in the cerebral cortex, in this work we performed a comprehensive investigation of its expression pattern during development and in the adulthood. Moreover, we assessed the role of neuroserpin in cortex formation by comparing cortical lamination and neuronal maturation between neuroserpin-deficient and control mice. Finally, we evaluated a possible regulatory role of neuroserpin at cortical synapses in neuroserpin-deficient mice. We observed that neuroserpin is expressed starting from the beginning of corticogenesis until adulthood throughout the cortex in both glutamatergic projection neurons and GABA-ergic interneurons. However, in the absence of neuroserpin we did not detect any alteration in cortical layer formation, in soma size, in dendritic length, and the ultrastructure. Furthermore no significant quantitative changes could be observed in the proteome of cortical synapses could be observed upon Neuroserpin deficiency. We conclude that, although strongly expressed in the cerebral cortex, absence of neuroserpin does not lead to developmental abnormalities, and does not perturb composition of the cortical synaptic proteome.
2021-02-23 | PXD022371 | Pride
Project description:Cerebral organoids â three-dimensional cultures of human cerebral tissue derived from pluripotent stem cells â have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and novel interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages, and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue in order to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures. 734 single-cell transcriptomes from human fetal neocortex or human cerebral organoids from multiple time points were analyzed in this study. All single cell samples were processed on the microfluidic Fluidigm C1 platform and contain 92 external RNA spike-ins. Fetal neocortex data were generated at 12 weeks post conception (chip 1: 81 cells; chip 2: 83 cells) and 13 weeks post conception (62 cells). Cerebral organoid data were generated from dissociated whole organoids derived from induced pluripotent stem cell line 409B2 (iPSC 409B2) at 33 days (40 cells), 35 days (68 cells), 37 days (71 cells), 41 days (74 cells), and 65 days (80 cells) after the start of embryoid body culture. Cerebral organoid data were also generated from microdissected cortical-like regions from H9 embryonic stem cell derived organoids at 53 days (region 1, 48 cells; region 2, 48 cells) or from iPSC 409B2 organoids at 58 days (region 3, 43 cells; region 4, 36 cells).
2015-12-07 | E-GEOD-75140 | biostudies-arrayexpress