scholarly journals Specification of diverse cell types during early neurogenesis of the mouse cerebellum

2018 ◽  
Author(s):  
John W. Wizeman ◽  
Qiuxia Guo ◽  
Elliot Wilion ◽  
James Y.H. Li
Keyword(s):  
Cell Fate ◽  
Developmental Trajectories ◽  
Ventricular Zone ◽  
Cell Types ◽  
Genome Wide ◽  
Integral Role ◽  
Cerebellar Cell ◽  
Early Neurogenesis ◽  
And Function ◽  
Developing Cerebellum

SUMMARYWe applied single-cell RNA sequencing to profile genome-wide gene expression in about 9,400 individual cerebellar cells from the mouse embryo at embryonic day 13.5. Reiterative clustering identified the major cerebellar cell types and subpopulations of different lineages. Through pseudotemporal ordering to reconstruct developmental trajectories, we identified novel transcriptional programs controlling cell fate specification of populations arising from the ventricular zone and the anterior rhombic lip, two distinct germinal zones of the embryonic cerebellum. Together, our data revealed cell-specific markers for studying the cerebellum, important specification decisions, and a number of previously unknown subpopulations that may play an integral role in the formation and function of the cerebellum. Importantly, we identified a potential mechanism of vermis formation, which is affected by multiple congenital cerebellar defects. Our findings will facilitate new discovery by providing insights into the molecular and cell type diversity in the developing cerebellum.

scholarly journals Specification of diverse cell types during early neurogenesis of the mouse cerebellum

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
John W Wizeman ◽  
Qiuxia Guo ◽  
Elliott M Wilion ◽  
James YH Li
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Developmental Trajectories ◽  
Ventricular Zone ◽  
Cell Types ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
Integral Role ◽  
Cerebellar Cell ◽  
And Function

We applied single-cell RNA sequencing to profile genome-wide gene expression in about 9400 individual cerebellar cells from the mouse embryo at embryonic day 13.5. Reiterative clustering identified the major cerebellar cell types and subpopulations of different lineages. Through pseudotemporal ordering to reconstruct developmental trajectories, we identified novel transcriptional programs controlling cell fate specification of populations arising from the ventricular zone and the rhombic lip, two distinct germinal zones of the embryonic cerebellum. Together, our data revealed cell-specific markers for studying the cerebellum, gene-expression cascades underlying cell fate specification, and a number of previously unknown subpopulations that may play an integral role in the formation and function of the cerebellum. Our findings will facilitate new discovery by providing insights into the molecular and cell type diversity in the developing cerebellum.

scholarly journals Molecular and functional characteristics of heart-valve interstitial cells

2007 ◽  
Vol 362 (1484) ◽  
pp. 1437-1443 ◽  
Author(s):  
Adrian H Chester ◽  
Patricia M Taylor
Keyword(s):  
Endothelial Cells ◽  
Heart Valve ◽  
Heart Valves ◽  
Cell Types ◽  
Interstitial Cells ◽  
Individual Characteristics ◽  
The Body ◽  
Integral Role ◽  
Valve Function ◽  
And Function

The cells that reside within valve cusps play an integral role in the durability and function of heart valves. There are principally two types of cells found in cusp tissue: the endothelial cells that cover the surface of the cusps and the interstitial cells (ICs) that form a network within the extracellular matrix (ECM) within the body of the cusp. Both cell types exhibit unique functions that are unlike those of other endothelial and ICs found throughout the body. The valve ICs express a complex pattern of cell-surface, cytoskeletal and muscle proteins. They are able to bind to, and communicate with, each other and the ECM. The endothelial cells on the outflow and inflow surfaces of the valve differ from one another. Their individual characteristics and functions reflect the fact that they are exposed to separate patterns of flow and pressure. In addition to providing a structural role in the valve, it is now known that the biological function of valve cells is important in maintaining the integrity of the cusps and the optimum function of the valve. In response to inappropriate stimuli, valve interstitial and endothelial cells may also participate in processes that lead to valve degeneration and calcification. Understanding the complex biology of valve interstitial and endothelial cells is an important requirement in elucidating the mechanisms that regulate valve function in health and disease, as well as setting a benchmark for the function of cells that may be used to tissue engineer a heart valve.

scholarly journals Body mass variations relate to fractionated functional brain hierarchies

2020 ◽  
Author(s):  
Bo-yong Park ◽  
Hyunjin Park ◽  
Filip Morys ◽  
Mansu Kim ◽  
Kyoungseob Byeon ◽  
...  
Keyword(s):  
Young Adults ◽  
Body Mass ◽  
Cell Types ◽  
Modular Architecture ◽  
Brain Organization ◽  
Functional Connectome ◽  
Genome Wide ◽  
Learning Techniques ◽  
Connectivity Patterns ◽  
Cerebellar Cell

AbstractVariations in body mass index (BMI) have been suggested to relate to atypical brain organization, yet connectome-level substrates of BMI and their neurobiological underpinnings remain unclear. Studying 325 healthy young adults, we examined association between functional connectome organization and BMI variations. We capitalized on connectome manifold learning techniques, which represent macroscale functional connectivity patterns along continuous hierarchical axes that dissociate low level and higher order brain systems. We observed an increased differentiation between unimodal and heteromodal association networks in individuals with higher BMI, indicative of an increasingly segregated modular architecture and a disruption in the hierarchical integration of different brain system. Transcriptomic decoding and subsequent gene enrichment analyses identified genes previously implicated in genome-wide associations to BMI and specific cortical, striatal, and cerebellar cell types. These findings provide novel insights for functional connectome substrates of BMI variations in healthy young adults and point to potential molecular associations.

scholarly journals Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors

2020 ◽  
Author(s):  
Shiri Kult ◽  
Tsviya Olender ◽  
Marco Osterwalder ◽  
Sharon Krief ◽  
Ronnie Blecher-Gonen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Single Molecule ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Regulatory Elements ◽  
Transcriptional Enhancer ◽  
Molecular Identity ◽  
And Function

AbstractThe connection between different tissues is vital for the development and function of any organs and systems. In the musculoskeletal system, the attachment of elastic tendons to stiff bones poses a mechanical challenge that is solved by the formation of a transitional tissue, which allows the transfer of muscle forces to the skeleton without tearing. Here, we show that tendon-to-bone attachment cells are bi-fated, activating a mixture of chondrocyte and tenocyte transcriptomes, which is regulated by sharing regulatory elements with these cells and by Krüppel-like factors transcription factors (KLF).To uncover the molecular identity of attachment cells, we first applied high-throughput RNA sequencing to murine humeral attachment cells. The results, which were validated by in situ hybridization and single-molecule in situ hybridization, reveal that attachment cells express hundreds of chondrogenic and tenogenic genes. In search for the underlying mechanism allowing these cells to express these genes, we performed ATAC sequencing and found that attachment cells share a significant fraction of accessible intergenic chromatin areas with either tenocytes or chondrocytes. Epigenomic analysis further revealed transcriptional enhancer signatures for the majority of these regions. We then examined a subset of these regions using transgenic mouse enhancer reporter. Results verified the shared activity of some of these enhancers, supporting the possibility that the transcriptome of attachment cells is regulated by enhancers with shared activities in tenocytes or chondrocytes. Finally, integrative chromatin and motif analyses, as well as the transcriptome data, indicated that KLFs are regulators of attachment cells. Indeed, blocking the expression of Klf2 and Klf4 in the developing limb mesenchyme led to abnormal differentiation of attachment cells, establishing these factors as key regulators of the fate of these cells.In summary, our findings show how the molecular identity of bi-fated attachment cells enables the formation of the unique transitional tissue that connect tendon to bone. More broadly, we show how mixing the transcriptomes of two cell types through shared enhancers and a dedicated set of transcription factors can lead to the formation of a new cell fate that connects them.

scholarly journals Single-cell transcriptomics identifies divergent developmental lineage trajectories during human pituitary development

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shu Zhang ◽  
Yueli Cui ◽  
Xinyi Ma ◽  
Jun Yong ◽  
Liying Yan ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Developmental Trajectories ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Human Pituitary ◽  
Pituitary Development ◽  
Physiological Processes ◽  
Distinct Cell ◽  
Transcriptional Landscape

Abstract The anterior pituitary gland plays a central role in regulating various physiological processes, including body growth, reproduction, metabolism and stress response. Here, we perform single-cell RNA-sequencing (scRNA-seq) of 4113 individual cells from human fetal pituitaries. We characterize divergent developmental trajectories with distinct transitional intermediate states in five hormone-producing cell lineages. Corticotropes exhibit an early intermediate state prior to full differentiation. Three cell types of the PIT-1 lineage (somatotropes, lactotropes and thyrotropes) segregate from a common progenitor coexpressing lineage-specific transcription factors of different sublineages. Gonadotropes experience two multistep developmental trajectories. Furthermore, we identify a fetal gonadotrope cell subtype expressing the primate-specific hormone chorionic gonadotropin. We also characterize the cellular heterogeneity of pituitary stem cells and identify a hybrid epithelial/mesenchymal state and an early-to-late state transition. Here, our results provide insights into the transcriptional landscape of human pituitary development, defining distinct cell substates and subtypes and illustrating transcription factor dynamics during cell fate commitment.

scholarly journals Retinal organoids: a window into human retinal development

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev189746
Author(s):  
Michelle O'Hara-Wright ◽  
Anai Gonzalez-Cordero
Keyword(s):  
Cell Fate ◽  
Developmental Trajectories ◽  
Retinal Development ◽  
Retinal Disease ◽  
Cell Types ◽  
Model Organisms ◽  
Retinal Cell ◽  
Human Retina ◽  
Cell Fate Decisions

ABSTRACTRetinal development and maturation are orchestrated by a series of interacting signalling networks that drive the morphogenetic transformation of the anterior developing brain. Studies in model organisms continue to elucidate these complex series of events. However, the human retina shows many differences from that of other organisms and the investigation of human eye development now benefits from stem cell-derived organoids. Retinal differentiation methods have progressed from simple 2D adherent cultures to self-organising micro-physiological systems. As models of development, these have collectively offered new insights into the previously unexplored early development of the human retina and informed our knowledge of the key cell fate decisions that govern the specification of light-sensitive photoreceptors. Although the developmental trajectories of other retinal cell types remain more elusive, the collation of omics datasets, combined with advanced culture methodology, will enable modelling of the intricate process of human retinogenesis and retinal disease in vitro.

scholarly journals Molecular Logic of Cellular Diversification in the Mammalian Cerebral Cortex

2020 ◽  
Author(s):  
Daniela J. Di Bella ◽  
Ehsan Habibi ◽  
Sun-Ming Yang ◽  
Robert R. Stickels ◽  
Juliana Brown ◽  
...  
Keyword(s):  
Single Cell ◽  
Developmental Trajectories ◽  
Cortical Cell ◽  
Cell Types ◽  
State Transitions ◽  
Evolutionary Constraint ◽  
Developmental Abnormalities ◽  
Molecular Logic ◽  
Dynamic Cell ◽  
And Function

ABSTRACTThe neocortex has an unparalleled diversity of cell types, which are generated during development through a series of temporally orchestrated events that are under tight evolutionary constraint and are critical for proper cortical assembly and function. However, the molecular logic that governs the establishment and organization of cortical cell types remains elusive, largely due to the large number of cell classes undergoing dynamic cell-state transitions over extended developmental timelines. Here, we have generated a comprehensive single-cell RNA-seq and single-cell ATAC-seq atlas of the developing mouse neocortex, sampled every day throughout embryonic corticogenesis. We computationally reconstruct developmental trajectories across the diversity of cortical cell classes, and infer the gene regulatory programs that accompany their lineage bifurcation decisions and their differentiation trajectories. Finally, we demonstrate how this developmental map pinpoints the origin of lineage-specific developmental abnormalities linked to aberrant corticogenesis in mutant animals. The data provides the first global picture of the regulatory mechanisms governing cellular diversification in the neocortex.

Could lncRNAs contribute to β-cell identity and its loss in Type 2 diabetes?

2013 ◽  
Vol 41 (3) ◽  
pp. 797-801 ◽  
Author(s):  
Timothy J. Pullen ◽  
Guy A. Rutter
Keyword(s):  
Type 2 Diabetes ◽  
Cell Mass ◽  
Cell Types ◽  
Human Populations ◽  
Β Cell ◽  
Cell Identity ◽  
Genome Wide ◽  
And Function

The progression of Type 2 diabetes is accompanied by diminishing islet β-cell mass and function. It has been proposed that β-cells are lost not only through apoptosis, but also by dedifferentiating into progenitor-like cells. There is therefore much interest in the mechanisms which define and maintain β-cell identity. The advent of genome-wide analyses of chromatin modifications has highlighted the role of epigenetic factors in determining cell identity. There is also evidence from both human populations and animal models for an epigenetic component in susceptibility to Type 2 diabetes. The mechanisms responsible for defining the epigenetic landscape in individual cell types are poorly understood, but there is growing evidence of a role for lncRNAs (long non-coding RNAs) in this process. In the present paper, we discuss some of the mechanisms through which lncRNAs may contribute to β-cell identity and Type 2 diabetes risk.

scholarly journals Inter-individual body mass variations relate to fractionated functional brain hierarchies

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Bo-yong Park ◽  
Hyunjin Park ◽  
Filip Morys ◽  
Mansu Kim ◽  
Kyoungseob Byeon ◽  
...  
Keyword(s):  
Young Adults ◽  
Body Mass ◽  
Functional Organization ◽  
Cell Types ◽  
Modular Architecture ◽  
Brain Organization ◽  
Genome Wide ◽  
Learning Techniques ◽  
Cerebellar Cell ◽  
The Brain

AbstractVariations in body mass index (BMI) have been suggested to relate to atypical brain organization, yet connectome-level substrates of BMI and their neurobiological underpinnings remain unclear. Studying 325 healthy young adults, we examined associations between functional connectivity and inter-individual BMI variations. We utilized non-linear connectome manifold learning techniques to represent macroscale functional organization along continuous hierarchical axes that dissociate low level and higher order brain systems. We observed an increased differentiation between unimodal and heteromodal association networks in individuals with higher BMI, indicative of a disrupted modular architecture and hierarchy of the brain. Transcriptomic decoding and gene enrichment analyses identified genes previously implicated in genome-wide associations to BMI and specific cortical, striatal, and cerebellar cell types. These findings illustrate functional connectome substrates of BMI variations in healthy young adults and point to potential molecular associations.

scholarly journals RT States: systematic annotation of the human genome using cell type-specific replication timing programs

2018 ◽  
Author(s):  
Axel Poulet ◽  
Ben Li ◽  
Tristan Dubos ◽  
Juan Carlos Rivera-Mulia ◽  
David M. Gilbert ◽  
...  
Keyword(s):  
Human Genome ◽  
Cell Fate ◽  
Developmental Stages ◽  
Replication Timing ◽  
Cell Types ◽  
Biological Properties ◽  
Biological Processes ◽  
Genomic Locus ◽  
Genome Wide ◽  
Fundamental Biological Process

ABSTRACTThe replication timing (RT) program has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows to characterize the RT program in the entire human genome in a high-throughput and high-resolution fashion. These experiments suggest that RT changes dynamically during development in coordination with gene activity. Since RT is such a fundamental biological process, we believe that an effective quantitative profile of the local RT program from a diverse set of cell types in various developmental stages and lineages can provide crucial biological insights for a genomic locus. In the present study, we explored recurrent and spatially coherent combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We found that a Hidden Markov Model with 15 hidden states provide a good model to describe these genome-wide RT profiling data. Each of the hidden state represents a unique combination of RT profiles across different cell types which we refer to as “RT states”. To understand the biological properties of these RT states, we inspected their relationship with chromatin states, gene expression, functional annotation and 3D chromosomal organization. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.AUTHOR SUMMARYThe replication timing (RT) program is an important cellular mechanism and has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows us to characterize the RT program in the entire human genome. Results from these experiments suggest that RT changes dynamically across different developmental stages. Since RT is such a fundamental biological process, we believe that the local RT program from a diverse set of cell types in various developmental stages can provide crucial biological insights for a genomic locus. In the present study, we explored combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We developed a statistical model consist of 15 “RT states” to describe these genome-wide RT profiling data. To understand the biological properties of these RT states, we inspected the relationship between RT states and other types of functional annotations of the genome. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.

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