An in vitro neurogenetics platform for precision disease modeling in the mouse DOI Creative Commons
Daniel Cortés, Mélanie Escudero, Austin C. Korgan

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(14)

Published: April 3, 2024

The power and scope of disease modeling can be markedly enhanced through the incorporation broad genetic diversity. introduction pathogenic mutations into a single inbred mouse strain sometimes fails to mimic human disease. We describe cross-species precision platform that exploits diversity bridge cell-based with whole organism analysis. developed universal protocol permitted robust reproducible neural differentiation genetically diverse pluripotent stem cell lines then carried out proof-of-concept study neurodevelopmental gene DYRK1A . Results in vitro reliably predicted effects background on Dyrk1a loss-of-function phenotypes vivo. Transcriptomic comparison responsive unresponsive strains identified molecular pathways conferring sensitivity or resilience Dyrk1a1A loss highlighted differential messenger RNA isoform usage as an important determinant response. This strategy provides powerful tool functional analysis candidate variants studies.

Language: Английский

Generation of human cerebral organoids with a structured outer subventricular zone DOI Creative Commons
Ryan Walsh, Raffaele Luongo, Elisa Giacomelli

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114031 - 114031

Published: April 1, 2024

Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and expansion neocortex. The in vitro generation oRG is essential to investigate underlying mechanisms human neocortical expansion. By activating STAT3 signaling pathway using leukemia inhibitory factor (LIF), which not expressed guided organoids, we define a organoid differentiation method from pluripotent stem (hPSCs) recapitulates pool into oSVZ. oSVZ comprises expressing specific markers such GFAP, LIFR, HOPX, closely matching fetal oRG. Finally, incorporating neural crest-derived LIF-producing pericytes organoids effects LIF treatment. These data indicate increasing cellular complexity microenvironment promotes emergence supports platform study hPSC-derived brain routinely.

Language: Английский

Citations

17
Molecular and cellular dynamics of the developing human neocortex DOI Creative Commons
Li Wang, Cheng Wang, Juan Moriano

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation1. Here we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 neocortical samples encompassing both prefrontal cortex primary visual cortex. These span five main developmental stages, ranging first trimester to adolescence. In parallel, performed spatial transcriptomic analysis on a subset illustrate organization intercellular communication. This atlas enables us catalogue cell-type-specific, age-specific area-specific regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification lineage-tracing experiments, have untangled lineage relationships among subtypes during neurogenesis-to-gliogenesis transition. We identified tripotential intermediate subtype—tripotential cells (Tri-IPCs)—that responsible for local production GABAergic neurons, oligodendrocyte precursor astrocytes. Notably, most glioblastoma resemble Tri-IPCs at level, suggesting that cancer hijack processes enhance growth heterogeneity. Furthermore, integrating our with large-scale genome-wide association study data, created disease-risk map highlighting enriched risk associated autism spectrum disorder in second-trimester intratelencephalic neurons. Our sheds light molecular dynamics developing neocortex. Tripotential are astrocytes

Language: Английский

Citations

5
Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain DOI
Changuk Chung, Xiaoxu Yang, Robert F. Hevner

et al.

Nature, Journal Year: 2024, Volume and Issue: 629(8011), P. 384 - 392

Published: April 10, 2024

Language: Английский

Citations

15
Molecular and cellular dynamics of the developing human neocortex at single-cell resolution DOI Creative Commons
Li Wang, Cheng Wang, Juan Moriano

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 16, 2024

The development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation

Language: Английский

Citations

13
Modelling human brain development and disease with organoids DOI
Marcella Birtele, Madeline A. Lancaster, Giorgia Quadrato

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Language: Английский

Citations

9
NOTCH, ERK, and SHH signaling respectively control the fate determination of cortical glia and olfactory bulb interneurons DOI Creative Commons

Yanjing Gao,

Mengge Sun, Tao Fu

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(9)

Published: Feb. 25, 2025

During cortical development, radial glial cells (neural stem cells) initially are neurogenic, generating intermediate progenitor that exclusively produce glutamatergic pyramidal neurons. Next, generate tripotential (Tri-IPCs) give rise to astrocytes and oligodendrocytes, olfactory bulb interneurons. The molecular mechanisms underlying the transition from neurogenesis gliogenesis, subsequent fate determination of astrocytes, interneurons, remain unclear. Here, we report extracellular signal-regulated kinase (ERK) signaling plays a fundamental role in promoting gliogenesis generation Tri-IPCs. Additionally, sonic hedgehog-smoothened-glioma-associated oncogene homolog (SHH-SMO-GLI) activator has an auxiliary function ERK during these processes. We further demonstrate that, Tri-IPCs, NOTCH is crucial for while prominent oligodendrocyte specification, SHH required provide evidence suggesting this mechanism conserved both mice humans. Finally, propose unifying principle mammalian gliogenesis.

Language: Английский

Citations

1
Neurorestorative Approaches for Ischemic Stroke DOI Creative Commons

Paulina Michór,

Lydia Renardson,

Shen Li

et al.

Neuroscience, Journal Year: 2024, Volume and Issue: 550, P. 69 - 78

Published: May 17, 2024

Despite recent advances in acute stroke management, most patients experiencing a will suffer from residual brain damage and functional impairment. Addressing those deficits would require neurorestoration, i.e., rebuilding tissue to repair the structural caused by stroke. However, there are major pathobiological, anatomical technological hurdles making neurorestorative approaches remarkably challenging, true neurorestoration after larger ischemic lesions could not yet be achieved. On other hand, has been steady advancement our understanding of limits regeneration adult mammalian as well fundamental organization growth during embryo- ontogenesis. This paralleled development novel animal models study stroke, biomaterials that can used support stem cell technologies. review gives detailed explanation so far preventing achievement It also describe concepts advancements biomaterial science, organoid culturing, modeling may enable investigation post-stroke translationally relevant setups. Finally, achievements experimental studies have potential starting point research activities eventually bring within reach.

Language: Английский

Citations

7
Spatial Single-cell Analysis Decodes Cortical Layer and Area Specification DOI Creative Commons
Xuyu Qian, Kyle Coleman,

Shunzhou Jiang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 5, 2024

The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens functionally specialized areas

Language: Английский

Citations

6
Single-cell genotyping and transcriptomic profiling in focal cortical dysplasia DOI Creative Commons
Stéphanie Baulac, Sara Baldassari, Esther Klingler

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: March 15, 2024

Abstract Focal cortical dysplasia type II (FCDII) is a malformation causing refractory epilepsy. FCDII arises from developmental somatic mutations in mTOR pathway genes, leading to focal dyslamination and abnormal cytomegalic cells. Which cell types carry pathogenic how they affect cell-type-specific transcriptional programs remains unknown. To address this question, here we combined single-nucleus genotyping transcriptomics morphologically-identified cells using surgical samples genetically-characterized patients. Mutations were predominantly detected glutamatergic neurons astrocytes only small fraction of mutated exhibited features, revealing incomplete penetrance FCDII-causing mutations. Moreover, identified dysregulations both non-mutated cells, including synapse neurodevelopment-related pathways, that may account for epilepsy, dysregulation mitochondrial metabolism pathways Together, these findings reveal cell-autonomous non-cell-autonomous mechanisms at play FCDII, towards the development precision therapies disorder.

Language: Английский

Citations

5
Brain development and bioenergetic changes DOI Creative Commons
Arjun Rajan, Ryann M. Fame

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 199, P. 106550 - 106550

Published: June 6, 2024

Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, discovery disease affecting individual stages development has revealed critical roles that play generating nervous system. Bioenergetic-dependent disorders include tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing cell-type specificity determine long-term effects bioenergetic mechanisms on form function. Here, we discuss metabolic progenitor specification, neuronal differentiation (neurogenesis), gliogenesis. In general, transitions between glycolysis oxidative phosphorylation are regulated early oncogenesis, reactive oxygen species (ROS) mitochondrial maturity later differentiation. We also how interface with developmental regulation other elements, including cerebrospinal fluid environment. While questions remain about interplay this review integrates current state known intersections health disease.

Language: Английский

Citations

4