Organoid single-cell genomic atlas uncovers human-specific features of brain development

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

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ISDN2012_0241: Developmental and evolutionary functions of a human‐specific gene duplication of srGAP2 during brain development

International Journal of Developmental Neuroscience ◽

10.1016/j.ijdevneu.2012.10.070 ◽

2012 ◽

Vol 30 (8) ◽

pp. 628-628

Author(s):

Cécile Charrier ◽

Kaumudi Joshi ◽

Takayuki Sassa ◽

Jaeda Coutinho‐Budd ◽

Nelle Lambert ◽

...

Keyword(s):

Gene Duplication ◽

Brain Development ◽

Specific Gene ◽

Human Specific

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Emergence of neuronal diversity during vertebrate brain development

10.1101/839860 ◽

2019 ◽

Author(s):

Bushra Raj ◽

Jeffrey A. Farrell ◽

Aaron McKenna ◽

Jessica L. Leslie ◽

Alexander F. Schier

Keyword(s):

Brain Development ◽

Single Cell ◽

Time Course ◽

Temporal Dynamics ◽

Cell Types ◽

Developmental Time ◽

Neural Progenitors ◽

Neuronal Diversity ◽

Gene Markers ◽

Vertebrate Brain

ABSTRACTNeurogenesis in the vertebrate brain comprises many steps ranging from the proliferation of progenitors to the differentiation and maturation of neurons. Although these processes are highly regulated, the landscape of transcriptional changes and progenitor identities underlying brain development are poorly characterized. Here, we describe the first developmental single-cell RNA-seq catalog of more than 200,000 zebrafish brain cells encompassing 12 stages from 12 hours post-fertilization to 15 days post-fertilization. We characterize known and novel gene markers for more than 800 clusters across these timepoints. Our results capture the temporal dynamics of multiple neurogenic waves from embryo to larva that expand neuronal diversity from ∼20 cell types at 12 hpf to ∼100 cell types at 15 dpf. We find that most embryonic neural progenitor states are transient and transcriptionally distinct from long-lasting neural progenitors of post-embryonic stages. Furthermore, we reconstruct cell specification trajectories for the retina and hypothalamus, and identify gene expression cascades and novel markers. Our analysis reveal that late-stage retinal neural progenitors transcriptionally overlap cell states observed in the embryo, while hypothalamic neural progenitors become progressively distinct with developmental time. These data provide the first comprehensive single-cell transcriptomic time course for vertebrate brain development and suggest distinct neurogenic regulatory paradigms between different stages and tissues.

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Molecular diversity and lineage commitment of human interneuron progenitors

10.1101/2021.05.13.444045 ◽

2021 ◽

Author(s):

Dmitry Velmeshev ◽

Manideep Chavali ◽

Tomasz Jan Nowakowski ◽

Mohini Bhade ◽

Simone Mayer ◽

...

Keyword(s):

Gene Expression ◽

Single Cell ◽

Autism Spectrum ◽

Lineage Commitment ◽

Proper Function ◽

Specific Gene ◽

Specific Cell ◽

Cortical Interneurons ◽

Human Specific ◽

Interneuron Development

Cortical interneurons are indispensable for proper function of neocortical circuits. Changes in interneuron development and function are implicated in human disorders, such as autism spectrum disorder and epilepsy. In order to understand human-specific features of cortical development as well as the origins of neurodevelopmental disorders it is crucial to identify the molecular programs underlying human interneuron development and subtype specification. Recent studies have explored gene expression programs underlying mouse interneuron specification and maturation. We applied single-cell RNA sequencing to samples of second trimester human ganglionic eminence and developing cortex to identify molecularly defined subtypes of human interneuron progenitors and immature interneurons. In addition, we integrated this data from the developing human ganglionic eminences and neocortex with single-nucleus RNA-seq of adult cortical interneurons in order to elucidate dynamic molecular changes associated with commitment of progenitors and immature interneurons to mature interneuron subtypes. By comparing our data with published mouse single-cell genomic data, we discover a number of divergent gene expression programs that distinguish human interneuron progenitors from mouse. Moreover, we find that a number of transcription factors expressed during prenatal development become restricted to adult interneuron subtypes in the human but not the mouse, and these adult interneurons express species- and lineage-specific cell adhesion and synaptic genes. Therefore, our study highlights that despite the similarity of main principles of cortical interneuron development and lineage commitment between mouse and human, human interneuron genesis and subtype specification is guided by species-specific gene programs, contributing to human-specific features of cortical inhibitory interneurons.

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115.3 Single-Cell Analysis of Adolescence and Other Critical Periods in Brain Development

Schizophrenia Bulletin ◽

10.1093/schbul/sbx021.160 ◽

2017 ◽

Vol 43 (suppl_1) ◽

pp. S61-S61

Author(s):

Steven McCarroll ◽

Evan Macosko ◽

Arpiar Saunders ◽

Melissa Goldman ◽

Laura Bortolin ◽

...

Keyword(s):

Brain Development ◽

Single Cell ◽

Single Cell Analysis ◽

Cell Analysis ◽

Critical Periods

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Single-cell genomic atlas of great ape cerebral organoids uncovers human-specific features of brain development

10.1101/685057 ◽

2019 ◽

Cited By ~ 4

Author(s):

Sabina Kanton ◽

Michael James Boyle ◽

Zhisong He ◽

Malgorzata Santel ◽

Anne Weigert ◽

...

Keyword(s):

Gene Expression ◽

Single Cell ◽

Expression Patterns ◽

Adult Brain ◽

The Other ◽

Specific Gene ◽

Great Ape ◽

Specific Gene Expression ◽

Gene Regulatory ◽

Human Specific

ABSTRACTThe human brain has changed dramatically since humans diverged from our closest living relatives, chimpanzees and the other great apes1–5. However, the genetic and developmental programs underlying this divergence are not fully understood6–8. Here, we have analyzed stem cell-derived cerebral organoids using single-cell transcriptomics (scRNA-seq) and accessible chromatin profiling (scATAC-seq) to explore gene regulatory changes that are specific to humans. We first analyze cell composition and reconstruct differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. We find that brain region composition varies in organoids from different iPSC lines, yet regional gene expression patterns are largely reproducible across individuals. We then analyze chimpanzee and macaque cerebral organoids and find that human neuronal development proceeds at a delayed pace relative to the other two primates. Through pseudotemporal alignment of differentiation paths, we identify human-specific gene expression resolved to distinct cell states along progenitor to neuron lineages in the cortex. We find that chromatin accessibility is dynamic during cortex development, and identify instances of accessibility divergence between human and chimpanzee that correlate with human-specific gene expression and genetic change. Finally, we map human-specific expression in adult prefrontal cortex using single-nucleus RNA-seq and find developmental differences that persist into adulthood, as well as cell state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene regulatory features that are unique to humans.

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Human-specific changes in two functional enhancers of FOXP2

10.1101/157016 ◽

2017 ◽

Author(s):

Antonio Benítez-Burraco ◽

Raúl Torres-Ruiz ◽

Pere Gelabert Xirinachs ◽

Carles Lalueza-Fox ◽

Sandra Rodríguez-Perales ◽

...

Keyword(s):

Vitamin D ◽

Transcription Factors ◽

Language Development ◽

Brain Development ◽

Binding Site ◽

Ancestral Allele ◽

Vitamin D Metabolism ◽

Development And Evolution ◽

Human Specific

AbstractTwo functional enhancers of FOXP2, a gene important for language development and evolution, exhibit several human-specific changes compared to extinct hominins that are located within the binding site for different transcription factors. Specifically, Neanderthals and Denisovans bear the ancestral allele in one position within the binding site for SMARCC1, involved in brain development and vitamin D metabolism. This change might have resulted in a different pattern of FOXP2 expression in our species compared to extinct hominins.

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Unraveling Human Brain Development and Evolution Using Organoid Models

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.737429 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sarah Fernandes ◽

Davis Klein ◽

Maria C. Marchetto

Keyword(s):

Human Brain ◽

Brain Development ◽

Brain Region ◽

Model Systems ◽

Transcriptional Signature ◽

Human Brain Development ◽

Advanced Stages ◽

Brain Organoid ◽

Development And Evolution ◽

Human Specific

Brain organoids are proving to be physiologically relevant models for studying human brain development in terms of temporal transcriptional signature recapitulation, dynamic cytoarchitectural development, and functional electrophysiological maturation. Several studies have employed brain organoid technologies to elucidate human-specific processes of brain development, gene expression, and cellular maturation by comparing human-derived brain organoids to those of non-human primates (NHPs). Brain organoids have been established from a variety of NHP pluripotent stem cell (PSC) lines and many protocols are now available for generating brain organoids capable of reproducibly representing specific brain region identities. Innumerous combinations of brain region specific organoids derived from different human and NHP PSCs, with CRISPR-Cas9 gene editing techniques and strategies to promote advanced stages of maturation, will successfully establish complex brain model systems for the accurate representation and elucidation of human brain development. Identified human-specific processes of brain development are likely vulnerable to dysregulation and could result in the identification of therapeutic targets or disease prevention strategies. Here, we discuss the potential of brain organoids to successfully model human-specific processes of brain development and explore current strategies for pinpointing these differences.

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