scholarly journals The cell fate controlling CLE40 peptide requires CNGC9 to trigger highly localized Ca2+ transients in Arabidopsis thaliana root meristems

2020 ◽  
Author(s):  
Maike Breiden ◽  
Vilde Olsson ◽  
Karine Gustavo-Pinto ◽  
Patrick Schultz ◽  
Gregoire Denay ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Root Meristem ◽  
Lateral Root Primordia ◽  
Cell Fate Decisions ◽  
Root Meristems ◽  
Gated Channel ◽  
Intracellular Ca ◽  
Secreted Peptides ◽  
Molecular Components

AbstractCommunication between plant cells and their biotic environment is largely dependent on the function of plasma membrane localized receptor-like kinases (RLKs). Major players in this communication within root meristems are secreted peptides, including CLAVATA3/EMBRYO SURROUNDING REGION40 (CLE40). In the distal root meristem, CLE40 acts through the receptor like kinase (RLK) ARABIDOPSIS CRINKLY4 (ACR4) and the leucine-rich repeat (LRR) RLK CLAVATA1 (CLV1) to promote cell differentiation. In the proximal meristem, CLE40 signalling requires the LRR receptor-like protein (RLP) CLAVATA2 (CLV2) and the membrane localized pseudokinase CORYNE (CRN), and serves to inhibit cell differentiation. The molecular components that act immediately downstream of the CLE40-activated receptors are not yet known. Here we show that active CLE40 signalling triggers the release of intracellular Ca2+ leading to increased cytosolic Ca2+ concentration ([Ca2+]cyt) in a subset of proximal root meristem cells. This rise in [Ca2+]cyt depends on the CYCLIC NUCLEOTIDE GATED CHANNEL 9 (CNGC9), CLV1, the CLV1-related BARELY ANY MERISTEM1 (BAM1), CLV2 and CRN. The precise function of changes in [Ca2+]cyt are not yet known, but might form a central part of a fine-tuned response to CLE40 peptide that serves to integrate root meristem growth with stem cell fate decisions and initiation of lateral root primordia.

scholarly journals Uncovering the mesendoderm gene regulatory network through multi-omic data integration

2020 ◽  
Author(s):  
Camden Jansen ◽  
Kitt D. Paraiso ◽  
Jeff J. Zhou ◽  
Ira L. Blitz ◽  
Margaret B. Fish ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Data Sets ◽  
List Type ◽  
Rna Seq ◽  
Data Types ◽  
Cell Fate Decisions ◽  
Gene Regulatory ◽  
Genome Scale ◽  
Omic Data

SummaryMesendodermal specification is one of the earliest events in embryogenesis, where cells first acquire distinct identities. Cell differentiation is a highly regulated process that involves the function of numerous transcription factors (TFs) and signaling molecules, which can be described with gene regulatory networks (GRNs). Cell differentiation GRNs are difficult to build because existing mechanistic methods are low-throughput, and high-throughput methods tend to be non-mechanistic. Additionally, integrating highly dimensional data comprised of more than two data types is challenging. Here, we use linked self-organizing maps to combine ChIP-seq/ATAC-seq with temporal, spatial and perturbation RNA-seq data from Xenopus tropicalis mesendoderm development to build a high resolution genome scale mechanistic GRN. We recovered both known and previously unsuspected TF-DNA/TF-TF interactions and validated through reporter assays. Our analysis provides new insights into transcriptional regulation of early cell fate decisions and provides a general approach to building GRNs using highly-dimensional multi-omic data sets.HighlightsBuilt a generally applicable pipeline to creating GRNs using highly-dimensional multi-omic data setsPredicted new TF-DNA/TF-TF interactions during mesendoderm developmentGenerate the first genome scale GRN for vertebrate mesendoderm and expanded the core mesendodermal developmental network with high fidelityDeveloped a resource to visualize hundreds of RNA-seq and ChIP-seq data using 2D SOM metaclusters.

scholarly journals MTG16 (CBFA2T3) represses E protein-dependent transcription to regulate colonic secretory cell differentiation, epithelial regeneration, and tumorigenesis

2021 ◽  
Author(s):  
Rachel E. Brown ◽  
Justin Jacobse ◽  
Shruti A. Anant ◽  
Koral M. Blunt ◽  
Bob Chen ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Mouse Model ◽  
Cell Fate ◽  
Protein Interactions ◽  
Protein Function ◽  
Colonic Epithelium ◽  
E Proteins ◽  
Cell Fate Decisions ◽  
Epithelial Regeneration ◽  
E Protein

Aberrant epithelial differentiation and regeneration pathways contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 interaction partners include E box-binding basic helix-loop-helix transcription factors (E proteins). MTG16-deficient mice exhibit worse colitis and increased tumor burden in inflammatory carcinogenesis. In this study, we sought to understand the role of MTG16 in colonic epithelial homeostasis and the mechanisms by which MTG16 protects the epithelium in colitis and CAC. We demonstrated that MTG16 deficiency enabled enteroendocrine cell differentiation from secretory precursor cells at the expense of goblet cells. Transcriptomic analysis implicated dysregulated E protein function in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation (Mtg16P209T), we established that enteroendocrine:goblet cell balance was dependent on MTG16:E protein interactions and that the shift in lineage allocation was associated with enhanced expression of Neurog3, the central driver of enteroendocrine lineage specification. Furthermore, Mtg16 was upregulated in the previously described Ascl2+, de-differentiating cells that replenish the stem cell compartment in response to colon injury. Mtg16 expression was also increased in dextran sulfate sodium (DSS)-treated mouse colon crypts and in IBD patients compared to unaffected controls. We determined that the effects of MTG16 in regeneration are also dependent on its repression of E proteins, as the colonic epithelium failed to regenerate following DSS-induced injury in our novel mutant mouse model. Finally, we revealed that uncoupling MTG16:E protein interactions contributes to the enhanced tumorigenicity in Mtg16-/- colon in the azoxymethane(AOM)/DSS-induced model of CAC. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colonic differentiation and regeneration.

scholarly journals Diversity of Nuclear Lamin A/C Action as a Key to Tissue-Specific Regulation of Cellular Identity in Health and Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Anna Malashicheva ◽  
Kseniya Perepelina
Keyword(s):  
Cell Differentiation ◽  
Identity Development ◽  
Cell Fate ◽  
Critical Role ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Cell Fate Decisions ◽  
Genes Encoding ◽  
Specific Regulation ◽  
Differentiation Status

A-type lamins are the main structural components of the nucleus, which are mainly localized at the nucleus periphery. First of all, A-type lamins, together with B-type lamins and proteins of the inner nuclear membrane, form a stiff structure—the nuclear lamina. Besides maintaining the nucleus cell shape, A-type lamins play a critical role in many cellular events, such as gene transcription and epigenetic regulation. Nowadays it is clear that lamins play a very important role in determining cell fate decisions. Various mutations in genes encoding A-type lamins lead to damages of different types of tissues in humans, collectively known as laminopathies, and it is clear that A-type lamins are involved in the regulation of cell differentiation and stemness. However, the mechanisms of this regulation remain unclear. In this review, we discuss how A-type lamins can execute their regulatory role in determining the differentiation status of a cell. We have summarized recent data focused on lamin A/C action mechanisms in regulation of cell differentiation and identity development of stem cells of different origin. We also discuss how this knowledge can promote further research toward a deeper understanding of the role of lamin A/C mutations in laminopathies.

scholarly journals True time series of gene expression from multinucleate single cells reveal essential information on the regulatory dynamics of cell differentiation

2020 ◽  
Author(s):  
Anna Pretschner ◽  
Sophie Pabel ◽  
Markus Haas ◽  
Monika Heiner ◽  
Wolfgang Marwan
Keyword(s):  
Gene Expression ◽  
Time Series ◽  
Cell Differentiation ◽  
Markov Chains ◽  
Cell Fate ◽  
Single Cells ◽  
Expression Patterns ◽  
Essential Information ◽  
Cell Fate Decisions ◽  
True Time

AbstractDynamics of cell fate decisions are commonly investigated by inferring temporal sequences of gene expression states by assembling snapshots of individual cells where each cell is measured once. Ordering cells according to minimal differences in expression patterns and assuming that differentiation occurs by a sequence of irreversible steps, yields unidirectional, eventually branching Markov chains with a single source node. In an alternative approach, we used multinucleate cells to follow gene expression taking true time series. Assembling state machines, each made from single-cell trajectories, gives a network of highly structured Markov chains of states with different source and sink nodes including cycles, revealing essential information on the dynamics of regulatory events. We argue that the obtained networks depict aspects of the Waddington landscape of cell differentiation and characterize them as reachability graphs that provide the basis for the reconstruction of the underlying gene regulatory network.

scholarly journals Graphene Nano-Fiber Composites for Enhanced Neuronal Differentiation of Human Mesenchymal Stem Cells†

2020 ◽  
Author(s):  
Sujata Mohanty ◽  
Krishan Gopal Jain ◽  
Sonali Rawat ◽  
Deepika Gupta ◽  
Pawan Raghav ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Fate ◽  
Human Mesenchymal Stem Cells ◽  
Cell Fate Decisions ◽  
Physiological Relevance ◽  
Nano Fiber ◽  
Intracellular Ca ◽  
Degree Of Differentiation ◽  
Poly Caprolactone

Abstract Graphene-based nanocomposites have been extensively employed to design biomimetic platforms epitomizing the structural and functional complexity of the tissue with increased robustness and physiological relevance. The adhesive and mechanical cues provided by such nanocomposite microenvironment kindles the cell fate decisions. Owing to their differentiation and regenerative potential, Human Mesenchymal Stem Cells (hMSCs) have proven to be a promising candidate for treating several neurodegenerative disorders. However, their degree of differentiation and its reproducibility is often jeopardized by multiple levels of heterogeneity, thereby compromising their translational utilization. Baffled at this crossroad, we designed a one-step approach to electrospin Poly-caprolactone (PCL) nanocomposite, with varying graphene concentrations, to capture, for the first time, the realms of their biocompatible and anisotropic characteristics, providing biomimetic platforms for improved differentiation of human bone marrow-derived MSCs (hMSCs) into neurons. Interestingly, PCL having 0.05% graphene (PCL-G0.05) showcased an ideal nano-topography with an unprecedented combination of guidance stimuli and substrates cues, aiding in enhanced differentiation of hMSCs into dopaminergic neurons (DA). These newly differentiated DA neurons were characterized at gene, protein, and functional levels and were seen to exhibit unique neuronal arborization, enhanced intracellular Ca2+ influx, and dopamine secretion, thereby opening new horizons for pre-clinical and clinical applications.

Overexpression of lunatic fringe does not affect epithelial cell differentiation in the developing mouse lung

2005 ◽  
Vol 288 (4) ◽  
pp. L672-L682 ◽  
Author(s):  
Minke van Tuyl ◽  
Freek Groenman ◽  
Maciek Kuliszewski ◽  
Ross Ridsdale ◽  
Jinxia Wang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Expression Patterns ◽  
Neuroendocrine Cells ◽  
Mouse Lung ◽  
Cell Fate Decisions ◽  
Lunatic Fringe ◽  
Hes1 Expression

The Notch/Notch-ligand pathway regulates cell fate decisions and patterning in various tissues. Several of its components are expressed in the developing lung, suggesting that this pathway is important for airway cellular patterning. Fringe proteins, which modulate Notch signaling, are crucial for defining morphogenic borders in several organs. Their role in controlling cellular differentiation along anterior-posterior axis of the airways is unknown. Herein, we report the temporal-spatial expression patterns of Lunatic fringe (Lfng) and Notch-regulated basic helix-loop-helix factors, Hes1 and Mash-1, during murine lung development. Lfng was only expressed during early development in epithelial cells lining the larger airways. Those epithelial cells also expressed Hes1, but at later gestation Hes1 expression was confined to epithelium lining the terminal bronchioles. Mash-1 displayed a very characteristic expression pattern. It followed neural crest migration in the early lung, whereas at later stages Mash-1 was expressed in lung neuroendocrine cells. To clarify whether Lfng influences airway cell differentiation, Lfng was overexpressed in distal epithelial cells of the developing mouse lung. Overexpression of Lfng did not affect spatial or temporal expression of Hes1 and Mash-1. Neuroendocrine CGRP and protein gene product 9.5 expression was not altered by Lfng overexpression. Expression of proximal ciliated (β-tubulin IV), nonciliated ( CCSP), and distal epithelial cell ( SP-C, T1α) markers also was not influenced by Lfng excess. Overexpression of Lfng had no effect on mesenchymal cell marker (α-sma, vWF, PECAM-1) expression. Collectively, the data suggest that Lunatic fringe does not play a significant role in determining cell fate in fetal airway epithelium.

scholarly journals Ultra-multiplexed analysis of single-cell dynamics reveals logic rules in differentiation

2019 ◽  
Vol 5 (4) ◽  
pp. eaav7959 ◽  
Author(s):  
Ce Zhang ◽  
Hsiung-Lin Tu ◽  
Gengjie Jia ◽  
Tanzila Mukhtar ◽  
Verdon Taylor ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Single Cell ◽  
Cell Fate ◽  
Single Cell Analysis ◽  
Single Cells ◽  
Critical Role ◽  
Stem Cell Differentiation ◽  
Cell Fate Decisions ◽  
Cellular Microenvironments

Dynamical control of cellular microenvironments is highly desirable to study complex processes such as stem cell differentiation and immune signaling. We present an ultra-multiplexed microfluidic system for high-throughput single-cell analysis in precisely defined dynamic signaling environments. Our system delivers combinatorial and time-varying signals to 1500 independently programmable culture chambers in week-long live-cell experiments by performing nearly 106 pipetting steps, where single cells, two-dimensional (2D) populations, or 3D neurospheres are chemically stimulated and tracked. Using our system and statistical analysis, we investigated the signaling landscape of neural stem cell differentiation and discovered “cellular logic rules” that revealed the critical role of signal timing and sequence in cell fate decisions. We find synergistic and antagonistic signal interactions and show that differentiation pathways are highly redundant. Our system allows dissection of hidden aspects of cellular dynamics and enables accelerated biological discovery.

scholarly journals Early cell fate decisions in the mouse embryo

Reproduction ◽  
2013 ◽  
Vol 145 (3) ◽  
pp. R65-R80 ◽  
Author(s):  
Néstor Saiz ◽  
Berenika Plusa
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Mouse Embryo ◽  
Molecular Mechanisms ◽  
Current Evidence ◽  
Cellular Interaction ◽  
Embryonic Cells ◽  
Developmental Potential ◽  
Cell Fate Decisions ◽  
Preimplantation Mouse

During mammalian preimplantation development, the fertilised egg gives rise to a group of pluripotent embryonic cells, the epiblast, and to the extraembryonic lineages that support the development of the foetus during subsequent phases of development. This preimplantation period not only accommodates the first cell fate decisions in a mammal's life but also the transition from a totipotent cell, the zygote, capable of producing any cell type in the animal, to cells with a restricted developmental potential. The cellular and molecular mechanisms governing the balance between developmental potential and lineage specification have intrigued developmental biologists for decades. The preimplantation mouse embryo offers an invaluable system to study cell differentiation as well as the emergence and maintenance of pluripotency in the embryo. Here we review the most recent findings on the mechanisms controlling these early cell fate decisions. The model that emerges from the current evidence indicates that cell differentiation in the preimplantation embryo depends on cellular interaction and intercellular communication. This strategy underlies the plasticity of the early mouse embryo and ensures the correct specification of the first mammalian cell lineages.

scholarly journals Regulatory Dynamics of Cell Differentiation Revealed by True Time Series From Multinucleate Single Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Anna Pretschner ◽  
Sophie Pabel ◽  
Markus Haas ◽  
Monika Heiner ◽  
Wolfgang Marwan
Keyword(s):  
Gene Expression ◽  
Time Series ◽  
Cell Differentiation ◽  
Markov Chains ◽  
Cell Fate ◽  
Single Cells ◽  
Expression Patterns ◽  
Essential Information ◽  
Cell Fate Decisions ◽  
True Time

Dynamics of cell fate decisions are commonly investigated by inferring temporal sequences of gene expression states by assembling snapshots of individual cells where each cell is measured once. Ordering cells according to minimal differences in expression patterns and assuming that differentiation occurs by a sequence of irreversible steps, yields unidirectional, eventually branching Markov chains with a single source node. In an alternative approach, we used multi-nucleate cells to follow gene expression taking true time series. Assembling state machines, each made from single-cell trajectories, gives a network of highly structured Markov chains of states with different source and sink nodes including cycles, revealing essential information on the dynamics of regulatory events. We argue that the obtained networks depict aspects of the Waddington landscape of cell differentiation and characterize them as reachability graphs that provide the basis for the reconstruction of the underlying gene regulatory network.

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