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

Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single-cell resolution DOI Creative Commons
Nicolò Caporale, Davide Castaldi, Marco Tullio Rigoli

et al.

Nature Methods, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Dissecting human neurobiology at high resolution and with mechanistic precision requires a major leap in scalability, given the need for experimental designs that include multiple individuals and, prospectively, population cohorts. To lay foundation this, we have developed benchmarked complementary strategies to multiplex brain organoids by pooling cells from different pluripotent stem cell (PSC) lines either during organoid generation (mosaic models) or before single-cell RNA sequencing (scRNA-seq) library preparation (downstream multiplexing). We also new computational method, SCanSNP, consensus call deconvolve identities, overcoming current criticalities doublets low-quality identification. validated both multiplexing methods charting neurodevelopmental trajectories resolution, thus linking specific individuals' genetic variation. Finally, modeled their scalability across combinations showed mosaic represent an enabling method high-throughput settings. Together, this suite of provides highly scalable resource disease neurodiversity modeling.

Language: Английский

Citations

4
A comparative view of human and mouse telencephalon inhibitory neuron development DOI
Changuk Chung, Joseph G. Gleeson, Joseph G. Gleeson

et al.

Development, Journal Year: 2025, Volume and Issue: 152(1)

Published: Jan. 1, 2025

ABSTRACT Human GABAergic inhibitory neurons (INs) in the telencephalon play crucial roles modulating neural circuits, generating cortical oscillations, and maintaining balance between excitation inhibition. The major IN subtypes are based on their gene expression profiles, morphological diversity circuit-specific functions. Although previous foundational work has established that INs originate ganglionic eminence regions mice, recent studies have questioned origins humans non-human primates. We review of mice compare with findings from primary human prenatal brain tissue culture experiments lineage analysis somatic variants neurotypical cadavers organoids. Together, these suggest potential primate- or human-specific processes may been overlooked mouse models could implications for disorders.

Language: Английский

Citations

0
Two independent translocation modes drive neural stem cell dissemination into the human fetal cortex DOI Creative Commons
Ryszard Wimmer,

Pauline Lestienne,

Christοphe Brunet

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Abstract The strong size increase of the human neocortex is supported both by amplification and basal translocation a neural stem cell population, radial glial cells (or bRG cells). Using live imaging second trimester fetal tissue cortical organoids, we identify two independent modes for colonization neocortex. On top an actomyosin-dependent movement called mitotic somal (MST), microtubule-dependent motion occurring during interphase, that call interphasic (IST). We show IST driven LINC complex, through nuclear envelope recruitment dynein motor its activator LIS1. Consequently, severely altered in LIS1 patient-derived organoids. also demonstrate MST occurs prometaphase spindle event. controlled rounding molecular pathway, via Moesin Vimentin, driving translocation. report 85% due to IST, total 0,67 mm per month gestation. Our work identifies how colonize cortex, further shows are conserved bRG-related migrating glioblastoma cells.

Language: Английский

Citations

0
Cortical arealization of interneurons defines shared and distinct molecular programs in developing human and macaque brains DOI Creative Commons
Xiangling Feng, Yingjie Gao,

Fan Chu

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 15, 2025

Cortical interneurons generated from ganglionic eminence via a long-distance journey of tangential migration display evident cellular and molecular differences across brain regions, which seeds the heterogeneous cortical circuitry in primates. However, whether such regional specifications are intrinsically encoded or gained through interactions with local milieu remains elusive. Here, we recruit 685,692 cerebral cortex subcortex including within developing human macaque species. Our integrative comparative analyses reveal that less transcriptomic alteration is accompanied by interneuron subdivisions, contrast to dramatic changes observed migration, mostly characterize specification for different destinations species divergence. Moreover, in-depth survey temporal regulation illustrates developmental dynamics cell types, e.g., employment CRH primate during late-fetal stage distinguishes their postnatal emergence mice, our entropy quantifications manifest diversities gradually increase along ages cortices. Overall, depict spatiotemporal features appended interneurons, providing new proxy understanding relationship between diversity functional progression. How gain Here authors telencephalons humans macaques shared distinct programs regulating arealization interneurons.

Language: Английский

Citations

0
Using cortical organoids to understand the pathogenesis of malformations of cortical development DOI Creative Commons
Kellen D. Winden,

Isabel Gisser,

Mustafa Şahin

et al.

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 18

Published: Jan. 15, 2025

Malformations of cortical development encompass a broad range disorders associated with abnormalities in corticogenesis. Widespread neuronal formation or migration can lead to small head size microcephaly disorganized placement cell types. Specific, localized malformations are termed focal dysplasias (FCD). Neurodevelopmental common all types the most prominent being refractory epilepsy, behavioral such as autism spectrum disorder (ASD), and learning disorders. Several genetic pathways have been these from control cycle cytoskeletal dynamics global variants growth factor signaling pathways, especially those interacting mechanistic target rapamycin (mTOR), FCDs. Despite advances understanding disorders, underlying developmental that lesion mechanisms through which defects cause specific neurological symptoms often remains unclear. One limitation is difficulty modeling animal models frequently do not faithfully mirror human phenotype. To circumvent this obstacle, many investigators turned three-dimensional stem brain, known organoids, because they recapitulate early neurodevelopmental processes. High throughput analysis organoids presents promising opportunity model pathophysiological processes across breadth development. In review, we highlight pathophysiology brain using organoid models.

Language: Английский

Citations

0
Emerging approaches to enhance human brain organoid physiology DOI Creative Commons
Anna Pagliaro, Benedetta Artegiani, Delilah Hendriks

et al.

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Brain organoids are important 3D models for studying human brain development, disease, and evolution. To overcome some of the existing limitations that affect organoid quality, reproducibility, characteristics, in vivo resemblance, current efforts directed to improve their physiological relevance by exploring different, yet interconnected, routes. In this review, these approaches latest developments discussed, including stem cell optimization, refining morphogen administration strategies, altering extracellular matrix (ECM) niche, manipulating tissue architecture mimic morphogenesis. Additionally, strategies increase diversity enhance maturation, such as establishing co-cultures, assembloids, xenotransplantation, reviewed. We explore how various factors can be tuned intermingled speculate on future avenues towards even more physiologically-advanced organoids.

Language: Английский

Citations

0
Metabolic Atlas of Early Human Cortex Identifies Regulators of Cell Fate Transitions DOI Creative Commons
Jessenya Mil, J Soto, Nedas Matulionis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Abstract Characterization of cell type emergence during human cortical development, which enables unique cognition, has focused primarily on anatomical and transcriptional characterizations. Metabolic processes in the brain that allow for rapid expansion, but contribute to vulnerability neurodevelopmental disorders, remain largely unexplored. We performed a variety metabolic assays primary tissue stem derived organoids observed dynamic changes core functions, including an unexpected increase glycolysis late neurogenesis. By depleting glucose levels organoids, we increased outer radial glia, astrocytes, inhibitory neurons. found pentose phosphate pathway (PPP) was impacted these experiments leveraged pharmacological genetic manipulations recapitulate glia fate changes. These data identify new role PPP modulating specification generate resource future exploration additional pathways development.

Language: Английский

Citations

0
Single-cell genotyping and transcriptomic profiling of mosaic focal cortical dysplasia DOI Creative Commons
Sara Baldassari, Esther Klingler,

Lucia Gomez Teijeiro

et al.

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

Published: April 30, 2025

Focal cortical dysplasia type II (FCDII) is a malformation causing refractory epilepsy. FCDII arises from developmental somatic activating 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 remain unknown. In the present study, we combined several single-nucleus genotyping transcriptomics approaches with spatial resolution surgical specimens patients genetically mosaic FCDII. Mutations were detected distinct types, including glutamatergic neurons astrocytes, small fraction of mutated cells exhibited features. Moreover, identified dysregulations both nonmutated cells, synapse- neurodevelopment-related pathways, that may account for epilepsy dysregulation mitochondrial metabolism pathways Together, these findings reveal cell-autonomous non-cell-autonomous features be leveraged precision medicine.

Language: Английский

Citations

0
Bioengineering innovations for neural organoids with enhanced fidelity and function DOI
Yubing Sun, Yoshiho Ikeuchi, Feng Guo

et al.

Cell stem cell, Journal Year: 2025, Volume and Issue: 32(5), P. 689 - 709

Published: May 1, 2025

Language: Английский

Citations

0
The Principle of Cortical Development and Evolution DOI Creative Commons
Zhengang Yang

Neuroscience Bulletin, Journal Year: 2024, Volume and Issue: unknown

Published: July 18, 2024

Abstract Human’s robust cognitive abilities, including creativity and language, are made possible, at least in large part, by evolutionary changes to the cerebral cortex. This paper reviews biology evolution of mammalian cortical radial glial cells (primary neural stem cells) introduces concept that a genetically step wise process, based on core molecular pathway already use, is process has molded neurogenesis. The mechanism, which been identified our recent studies, extracellular signal-regulated kinase (ERK)-bone morphogenic protein 7 (BMP7)-GLI3 repressor form (GLI3R)-sonic hedgehog (SHH) positive feedback loop. Additionally, I propose basis for dwarfism, exemplified lissencephalic mouse originated from larger gyrencephalic ancestor, an increase SHH signaling glia, antagonizes ERK-BMP7 signaling. Finally, that: (1) not key regulator primate expansion folding; (2) human do generate neocortical interneurons; (3) human-specific genes may be essential most expansion. hope this review assists colleagues field, guiding research address gaps understanding development evolution.

Language: Английский

Citations

3