scholarly journals COMPASS Family Histone Methyltransferase ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signalling

2018 ◽  
Author(s):  
Liang Li ◽  
Xiangbin Ruan ◽  
Chang Wen ◽  
Pan Chen ◽  
Wei Liu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Histone Methyltransferase ◽  
Projection Neurons ◽  
Cell Fate Specification ◽  
Cortical Projection ◽  
Proliferation Ability ◽  
Late Stages

AbstractCell fate specification in neural progenitor cells (NPCs) is orchestrated via extrinsic and intrinsic molecular programs, and histone methylation in these decisions has been ascribed to a crucial function regulating gene expression. Here, we show that the COMPASS family histone methyltransferase co-factor ASH2L is required in NPCs proliferation and upper layer cortical projection neurons production and position. Deletion of Ash2l impairs trimethylation of H3K4 and transcriptional machinery specifically for subsets of Wnt-β-catenin signalling, disrupting their transcription and consequently inhibiting the proliferation ability of NPCs in late stages of neurogenesis. Consistently, Ash2l conditional mutants exhibit thinning neocortex with reduced upper layer neurons and altered neuronal position. Moreover, overexpressing β-catenin after Ash2l elimination or knockdown can rescue the proliferation deficiency of NPCs both in vivo and in vitro. These results demonstrate an essential and highly specific role for Ash2l in controlling NPCs proliferation and late-born neurons lamination in corticogenesis via transcriptionally regulating Wnt-β-catenin signalling, and provide clues to how the COMPASS family epigenetic factors coordinate cell fate determination during cortex development.

Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3637-3650 ◽  
Author(s):  
C.P. Austin ◽  
D.E. Feldman ◽  
J.A. Ida ◽  
C.L. Cepko
Keyword(s):  
Cell Fate ◽  
Ganglion Cells ◽  
Notch Pathway ◽  
Cell Types ◽  
Projection Neurons ◽  
Specific Cell ◽  
Vitro Assay ◽  
Notch Activity

The first cells generated during development of the vertebrate retina are the ganglion cells, the projection neurons of the retina. Although they are one of the most intensively studied cell types within the central nervous system, little is known of the mechanisms that determine ganglion cell fate. We demonstrate that ganglion cells are selected from a large group of competent progenitors that comprise the majority of the early embryonic retina and that differentiation within this group is regulated by Notch. Notch activity in vivo was diminished using antisense oligonucleotides or augmented using a retrovirally transduced constitutively active allele of Notch. The number of ganglion cells produced was inversely related to the level of Notch activity. In addition, the Notch ligand Delta inhibited retinal progenitors from differentiating as ganglion cells to the same degree as did activated Notch in an in vitro assay. These results suggest a conserved strategy for neurogenesis in the retina and describe a versatile in vitro and in vivo system with which to examine the action of the Notch pathway in a specific cell fate decision in a vertebrate.

scholarly journals Differential chromatin accessibility in developing projection neurons is correlated with transcriptional regulation of cell fate

2019 ◽  
Author(s):  
Whitney E. Heavner ◽  
Shaoyi Ji ◽  
James H. Notwell ◽  
Ethan S. Dyer ◽  
Alex M. Tseng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Expression Profiles ◽  
Chromatin Accessibility ◽  
Transcriptional Networks ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Functional Features

AbstractWe are only just beginning to catalog the vast diversity of cell types in the cerebral cortex. Such categorization is a first step toward understanding how diversification relates to function. All cortical projection neurons arise from a uniform pool of progenitor cells that lines the ventricles of the forebrain. It is still unclear how these progenitor cells generate the more than fifty unique types of mature cortical projection neurons defined by their distinct gene expression profiles. Here we compare gene expression and chromatin accessibility of two subclasses of projection neurons with divergent morphological and functional features as they develop in the mouse brain between embryonic day 13 and postnatal day 5 in order to identify transcriptional networks that diversity neuron cell fate. We find groups of transcription factors whose expression is correlated with chromatin accessibility, transcription factor binding motifs, and lncRNAs that define each subclass and validate the function of a family of novel candidate genes in vitro. Our multidimensional approach reveals that subclass-specific chromatin accessibility is significantly correlated with gene expression, providing a resource for generating new specific genetic drivers and revealing regions of the genome that are particularly susceptible to harmful genetic mutations by virtue of their correlation with important developmental genes.

scholarly journals The +TIP Navigator-1 is an actin–microtubule crosslinker that regulates axonal growth cone motility

2020 ◽  
Vol 219 (9) ◽  
Author(s):  
Carlos Sánchez-Huertas ◽  
Marion Bonhomme ◽  
Amandine Falco ◽  
Christine Fagotto-Kaufmann ◽  
Jeffrey van Haren ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Actin Filaments ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Cortical Projection ◽  
Axonal Growth Cone ◽  
Neuronal Functions ◽  
Developing Nervous System

Microtubule (MT) plus-end tracking proteins (+TIPs) are central players in the coordination between the MT and actin cytoskeletons in growth cones (GCs) during axon guidance. The +TIP Navigator-1 (NAV1) is expressed in the developing nervous system, yet its neuronal functions remain poorly elucidated. Here, we report that NAV1 controls the dynamics and motility of the axonal GCs of cortical neurons in an EB1-dependent manner and is required for axon turning toward a gradient of netrin-1. NAV1 accumulates in F-actin–rich domains of GCs and binds actin filaments in vitro. NAV1 can also bind MTs independently of EB1 in vitro and crosslinks nonpolymerizing MT plus ends to actin filaments in axonal GCs, preventing MT depolymerization in F-actin–rich areas. Together, our findings pinpoint NAV1 as a key player in the actin–MT crosstalk that promotes MT persistence at the GC periphery and regulates GC steering. Additionally, we present data assigning to NAV1 an important role in the radial migration of cortical projection neurons in vivo.

Caenorhabditis elegans lin-25: A Study of Its Role in Multiple Cell Fate Specification Events Involving Ras and the Identification and Characterization of Evolutionarily Conserved Domains

Genetics ◽  
2000 ◽  
Vol 156 (3) ◽  
pp. 1083-1096
Author(s):  
Lars Nilsson ◽  
Teresa Tiensuu ◽  
Simon Tuck
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Nuclear Translocation ◽  
Cell Fate Specification ◽  
Sequence Comparisons ◽  
Vulval Development ◽  
Fate Specification ◽  
C Elegans

Abstract Caenorhabditis elegans lin-25 functions downstream of let-60 ras in the genetic pathway for the induction of the 1° cell fate during vulval development and encodes a novel 130-kD protein. The biochemical activity of LIN-25 is presently unknown, but the protein appears to function together with SUR-2, whose human homologue binds to Mediator, a protein complex required for transcriptional regulation. We describe here experiments that indicate that, besides its role in vulval development, lin-25 also participates in the fate specification of a number of other cells in the worm that are known to require Ras-mediated signaling. We also describe the cloning of a lin-25 orthologue from C. briggsae. Sequence comparisons suggest that the gene is evolving relatively rapidly. By characterizing the molecular lesions associated with 10 lin-25 mutant alleles and by assaying in vivo the activity of mutants lin-25 generated in vitro, we have identified three domains within LIN-25 that are required for activity or stability. We have also identified a sequence that is required for efficient nuclear translocation. We discuss how lin-25 might act in cell fate specification in C. elegans within the context of models for lin-25 function in cell identity and cell signaling.

Analysis of the Dynamics of the Electric Capacitance of a Cell Monolayer at the Late Stages of Caco-2 cell Differentiation

2019 ◽  
Vol 35 (6) ◽  
pp. 87-90
Author(s):  
S.V. Nikulin ◽  
V.A. Petrov ◽  
D.A. Sakharov
Keyword(s):  
Impedance Spectroscopy ◽  
Cell Monolayer ◽  
Microfluidic Chips ◽  
Russian Science ◽  
Electric Capacitance ◽  
A Cell ◽  
Static Conditions ◽  
Late Stages

The real-time monitoring of electric capacitance (impedance spectroscopy) allowed obtaining evidence that structures which look like intestinal villi can be formed during the cultivation under static conditions as well as during the cultivation in microfluidic chips. It was shown in this work via transcriptome analysis that the Hh signaling pathway is involved in the formation of villus-like structures in vitro, which was previously shown for their formation in vivo. impedance spectroscopy, intestine, villi, electric capacitance, Hh The study was funded by the Russian Science Foundation (Project 16-19-10597).

scholarly journals Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Wang ◽  
Liming Zhu ◽  
Mei Guo ◽  
Gang Sun ◽  
Kun Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
B Cell Lymphoma ◽  
Histone Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Cancer Cell Apoptosis ◽  
Active Transcription

AbstractWHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in CRC patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What’s more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.

The Drosophila extramacrochaetae protein antagonizes sequence-specific DNA binding by daughterless/achaete-scute protein complexes

Development ◽  
1991 ◽  
Vol 113 (1) ◽  
pp. 245-255 ◽  
Author(s):  
M. Van Doren ◽  
H.M. Ellis ◽  
J.W. Posakony
Keyword(s):  
Dna Binding ◽  
Cell Fate ◽  
Protein Complexes ◽  
Competitive Inhibitor ◽  
Binding Activity ◽  
Regulatory Function ◽  
Biochemical Basis ◽  
Dna Binding Activity

In Drosophila, a group of regulatory proteins of the helix-loop-helix (HLH) class play an essential role in conferring upon cells in the developing adult epidermis the competence to give rise to sensory organs. Proteins encoded by the daughterless (da) gene and three genes of the achaete-scute complex (AS-C) act positively in the determination of the sensory organ precursor cell fate, while the extramacrochaetae (emc) and hairy (h) gene products act as negative regulators. In the region upstream of the achaete gene of the AS-C, we have identified three ‘E box’ consensus sequences that are bound specifically in vitro by hetero-oligomeric complexes consisting of the da protein and an AS-C protein. We have used this DNA-binding activity to investigate the biochemical basis of the negative regulatory function of emc. Under the conditions of our experiments, the emc protein, but not the h protein, is able to antagonize specifically the in vitro DNA-binding activity of da/AS-C and putative da/da protein complexes. We interpret these results as follows: the heterodimerization capacity of the emc protein (conferred by its HLH domain) allows it to act in vivo as a competitive inhibitor of the formation of functional DNA-binding protein complexes by the da and AS-C proteins, thereby reducing the effective level of their transcriptional regulatory activity within the cell.

scholarly journals Stiffness Regulates Intestinal Stem Cell Fate

2021 ◽  
Author(s):  
Shijie He ◽  
Peng Lei ◽  
Wenying Kang ◽  
Priscilla Cheung ◽  
Tao Xu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Nuclear Translocation ◽  
Goblet Cells ◽  
Metabolic Phenotype ◽  
Hydrogel Matrix ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
The Impact

SummaryDoes fibrotic gut stiffening caused by inflammatory bowel diseases (IBD) direct the fate of intestinal stem cells (ISCs)? To address this question we first developed a novel long-term culture of quasi-3D gut organoids plated on hydrogel matrix of varying stiffness. Stiffening from 0.6kPa to 9.6kPa significantly reduces Lgr5high ISCs and Ki67+ progenitor cells while promoting their differentiation towards goblet cells. These stiffness-driven events are attributable to YAP nuclear translocation. Matrix stiffening also extends the expression of the stemness marker Olfactomedin 4 (Olfm4) into villus-like regions, mediated by cytoplasmic YAP. We next used single-cell RNA sequencing to generate for the first time the stiffness-regulated transcriptional signatures of ISCs and their differentiated counterparts. These signatures confirm the impact of stiffening on ISC fate and additionally suggest a stiffening-induced switch in metabolic phenotype, from oxidative phosphorylation to glycolysis. Finally, we used colon samples from IBD patients as well as chronic colitis murine models to confirm the in vivo stiffening-induced epithelial deterioration similar to that observed in vitro. Together, these results demonstrate stiffness-dependent ISC reprograming wherein YAP nuclear translocation diminishes ISCs and Ki67+ progenitors and drives their differentiation towards goblet cells, suggesting stiffening as potential target to mitigate gut epithelial deterioration during IBD.

scholarly journals Prediction and control of symmetry breaking in embryoid bodies by environment and signal integration

2018 ◽  
Author(s):  
Naor Sagy ◽  
Shaked Slovin ◽  
Maya Allalouf ◽  
Maayan Pour ◽  
Gaya Savyon ◽  
...  
Keyword(s):  
Symmetry Breaking ◽  
Cell Fate ◽  
Developmental Process ◽  
Primitive Streak ◽  
Early Embryo ◽  
Embryoid Bodies ◽  
Neighboring Cell ◽  
Contact Points

AbstractDuring early embryogenesis, mechanical signals, localized biochemical signals and neighboring cell layers interaction coordinate around anteroposterior axis determination and symmetry breaking. Deciphering their relative roles, which are hard to tease apart in vivo, will enhance our understanding of how these processes are driven. In recent years, in vitro 3D models of early mammalian development, such as embryoid bodies (EBs) and gastruloids, were successful in mimicking various aspects of the early embryo, providing high throughput accessible systems for studying the basic rules shaping cell fate and morphology during embryogenesis. Using Brachyury (Bry), a primitive streak and mesendoderm marker in EBs, we study how contact, biochemical and neighboring cell cues affect the positioning of a primitive streak-like locus, determining the AP axis. We show that a Bry-competent layer must be formed in the EB before Bry expression initiates, and that Bry onset locus selection depends on contact points of the EB with its surrounding. We can maneuver Bry onset to occur at a specific locus, a few loci, or in an isotropic peripheral pattern. By spatially separating contact and biochemical signal sources, we show these two modalities can be integrated by the EB to generate a single Bry locus. Finally, we show Foxa2+ cells are predictive of the future location of Bry onset, demonstrating an earlier symmetry-breaking event. By delineating the temporal signaling pathway dependencies of Bry and Foxa2, we were able to selectively abolish either, or spatially decouple the two cell types during EB differentiation. These findings demonstrate multiple inputs integration during an early developmental process, and may prove valuable in directing in vitro differentiation.

scholarly journals Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

2021 ◽  
Vol 22 (17) ◽  
pp. 9517
Author(s):  
Gianluca Testa ◽  
Giorgia Di Benedetto ◽  
Fabiana Passaro
Keyword(s):  
Cell Fate ◽  
Disease Modeling ◽  
Heart Diseases ◽  
Cellular Reprogramming ◽  
Cardiac Cell ◽  
New Paradigm ◽  
Cardiovascular Research ◽  
Injured Myocardium

The adult human heart can only adapt to heart diseases by starting a myocardial remodeling process to compensate for the loss of functional cardiomyocytes, which ultimately develop into heart failure. In recent decades, the evolution of new strategies to regenerate the injured myocardium based on cellular reprogramming represents a revolutionary new paradigm for cardiac repair by targeting some key signaling molecules governing cardiac cell fate plasticity. While the indirect reprogramming routes require an in vitro engineered 3D tissue to be transplanted in vivo, the direct cardiac reprogramming would allow the administration of reprogramming factors directly in situ, thus holding great potential as in vivo treatment for clinical applications. In this framework, cellular reprogramming in partnership with nanotechnologies and bioengineering will offer new perspectives in the field of cardiovascular research for disease modeling, drug screening, and tissue engineering applications. In this review, we will summarize the recent progress in developing innovative therapeutic strategies based on manipulating cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.

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