scholarly journals Notch Signaling in Development, Tissue Homeostasis, and Disease

2017 ◽  
Vol 97 (4) ◽  
pp. 1235-1294 ◽  
Author(s):  
Chris Siebel ◽  
Urban Lendahl
Keyword(s):  
Notch Signaling ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Tissue Homeostasis ◽  
Cell Fates ◽  
Signaling Mechanism ◽  
Transmembrane Receptors ◽  
Notch Gene ◽  
Broad Variety

Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell communication, where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed cell. Originally discovered through mutations in Drosophila more than 100 yr ago, and with the first Notch gene cloned more than 30 yr ago, we are still gaining new insights into the broad effects of Notch signaling in organisms across the metazoan spectrum and its requirement for normal development of most organs in the body. In this review, we provide an overview of the Notch signaling mechanism at the molecular level and discuss how the pathway, which is architecturally quite simple, is able to engage in the control of cell fates in a broad variety of cell types. We discuss the current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation. Finally, we explore the emerging field of Notch in the control of tissue homeostasis, with examples from skin, liver, lung, intestine, and the vasculature.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis

Development ◽  
2000 ◽  
Vol 127 (17) ◽  
pp. 3865-3876
Author(s):  
M.S. Rones ◽  
K.A. McLaughlin ◽  
M. Raffin ◽  
M. Mercola
Keyword(s):  
Gene Expression ◽  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Cell Types ◽  
Myocardial Cell ◽  
Dominant Negative ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Heart Field

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326–340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

Exosomes and cardiovascular cell–cell communication

2018 ◽  
Vol 62 (2) ◽  
pp. 193-204 ◽  
Author(s):  
Adam J. Poe ◽  
Anne A. Knowlton
Keyword(s):  
Biological Fluids ◽  
Cell Communication ◽  
Cell Types ◽  
Cardiac Cells ◽  
The Body ◽  
Biologically Active ◽  
Surrounding Tissue ◽  
Intercellular Signaling ◽  
Cardiac Damage ◽  
Almost All

Exosomes have become an important player in intercellular signaling. These lipid microvesicles can stably transfer miRNA, protein, and other molecules between cells and circulate throughout the body. Exosomes are released by almost all cell types and are present in most if not all biological fluids. The biologically active cargo carried by exosomes can alter the phenotype of recipient cells. Exosomes increasingly are recognized as having an important role in the progression and treatment of cardiac disease states. Injured cardiac cells can release exosomes with important pathological effects on surrounding tissue, in addition to effecting other organs. But of equal interest is the possible benefit(s) conferred by exosomes released from stem cells for use in treatment and possible repair of cardiac damage.

scholarly journals Proteomics identifies differences in fibrotic potential of extracellular vesicles from human tendon and muscle fibroblasts

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Ching-Yan Chloé Yeung ◽  
Erwin M. Schoof ◽  
Michal Tamáš ◽  
Abigail L. Mackey ◽  
Michael Kjaer
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Vesicles ◽  
Human Fibroblasts ◽  
Cell Communication ◽  
The Body ◽  
Tissue Homeostasis ◽  
Force Transmission ◽  
Healthy Human ◽  
Tendon Fibroblast ◽  
Human Tendon

Abstract Background Fibroblasts are the powerhouses responsible for the production and assembly of extracellular matrix (ECM). Their activity needs to be tightly controlled especially within the musculoskeletal system, where changes to ECM composition affect force transmission and mechanical loading that are required for effective movement of the body. Extracellular vesicles (EVs) are a mode of cell-cell communication within and between tissues, which has been largely characterised in cancer. However, it is unclear what the role of healthy fibroblast-derived EVs is during tissue homeostasis. Methods Here, we performed proteomic analysis of small EVs derived from primary human muscle and tendon cells to identify the potential functions of healthy fibroblast-derived EVs. Results Mass spectrometry-based proteomics revealed comprehensive profiles for small EVs released from healthy human fibroblasts from different tissues. We found that fibroblast-derived EVs were more similar than EVs from differentiating myoblasts, but there were significant differences between tendon fibroblast and muscle fibroblast EVs. Small EVs from tendon fibroblasts contained higher levels of proteins that support ECM synthesis, including TGFβ1, and muscle fibroblast EVs contained proteins that support myofiber function and components of the skeletal muscle matrix. Conclusions Our data demonstrates a marked heterogeneity among healthy fibroblast-derived EVs, indicating shared tasks between EVs of skeletal muscle myoblasts and fibroblasts, whereas tendon fibroblast EVs could play a fibrotic role in human tendon tissue. These findings suggest an important role for EVs in tissue homeostasis of both tendon and skeletal muscle in humans.

scholarly journals Numb Proteins Specify Asymmetric Cell Fates via an Endocytosis- and Proteasome-Independent Pathway

2005 ◽  
Vol 25 (8) ◽  
pp. 2899-2909 ◽  
Author(s):  
Haiyan Tang ◽  
Santiago B. Rompani ◽  
Joshua B. Atkins ◽  
Yan Zhou ◽  
Thomas Osterwalder ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Cell Communication ◽  
Cell Fates ◽  
Binding Motifs ◽  
Protein Levels ◽  
Daughter Cells ◽  
Notch Protein ◽  
Evolutionarily Conserved ◽  
Asymmetric Divisions

ABSTRACT Numb proteins are evolutionarily conserved signaling molecules that make the daughter cells different after asymmetric divisions by segregating to only one daughter. They contain distinct binding motifs for α-adaptin (α-Ada) and proteins with Eps15 homology (EH) domains, which regulate endocytosis, and for E3 ubiquitin ligases, which target proteins for proteasome-mediated degradation. In Drosophila melanogaster, Numb acts by inhibiting Notch activity to cause a bias in Notch-mediated cell-cell communication. These findings have led to the hypothesis that Numb modulates Notch signaling by using endocytosis and proteasomes to directly reduce Notch protein levels at the cell surface. Here we show that two Drosophila EH proteins, Eps15 homologue 1 (EH1) and the dynamin-associated 160-kDa protein (Dap160), negatively regulate Notch signaling. However, neither elimination of the binding motifs for endocytic proteins nor simultaneous reduction of proteasome activity affects the activity of Numb proteins. Our findings indicate that an endocytosis- and proteasome-independent pathway may mediate Numb signaling in asymmetric cell fate specification.

Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation

Development ◽  
2001 ◽  
Vol 128 (4) ◽  
pp. 491-502 ◽  
Author(s):  
B. McCright ◽  
X. Gao ◽  
L. Shen ◽  
J. Lozier ◽  
Y. Lan ◽  
...  
Keyword(s):  
Genetic Interaction ◽  
Signal Transduction Pathway ◽  
Intercellular Signaling ◽  
Signaling Mechanism ◽  
Transmembrane Receptors ◽  
Targeted Mutation ◽  
Evolutionarily Conserved ◽  
Notch Gene ◽  
Glomerular Development

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the in vivo role of the Notch2 gene, we constructed a targeted mutation, Notch2(del1). Unexpectedly, we found that alternative splicing of the Notch2(del1) mutant allele leads to the production of two different in-frame transcripts that delete either one or two EGF repeats of the Notch2 protein, suggesting that this allele is a hypomorphic Notch2 mutation. Mice homozygous for the Notch2(del1) mutation died perinatally from defects in glomerular development in the kidney. Notch2(del1)/Notch2(del1)mutant kidneys were hypoplastic and mutant glomeruli lacked a normal capillary tuft. The Notch ligand encoded by the Jag1 gene was expressed in developing glomeruli in cells adjacent to Notch2-expressing cells. We show that mice heterozygous for both the Notch2(del1) and Jag1(dDSL) mutations exhibit a glomerular defect similar to, but less severe than, that of Notch2(del1)/Notch2(del1)homozygotes. The co-localization and genetic interaction of Jag1 and Notch2 imply that this ligand and receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2(del1)/Notch2(del1)homozygotes also display myocardial hypoplasia, edema and hyperplasia of cells associated with the hyaloid vasculature of the eye. These data identify novel developmental roles for Notch2 in kidney, heart and eye development.

Dendritic trafficking for neuronal growth and plasticity

2013 ◽  
Vol 41 (6) ◽  
pp. 1365-1382 ◽  
Author(s):  
Michael D. Ehlers
Keyword(s):  
Cell Biology ◽  
Neural Circuit ◽  
Cell Communication ◽  
Neuronal Cell ◽  
Cell Types ◽  
The Body ◽  
Plastic Properties ◽  
Electrophysiological Properties ◽  
Differentiated Cells ◽  
Unique Cell

Among the largest cells in the body, neurons possess an immense surface area and intricate geometry that poses many unique cell biological challenges. This morphological complexity is critical for neural circuit formation and enables neurons to compartmentalize cell–cell communication and local intracellular signalling to a degree that surpasses other cell types. The adaptive plastic properties of neurons, synapses and circuits have been classically studied by measurement of electrophysiological properties, ionic conductances and excitability. Over the last 15 years, the field of synaptic and neural electrophysiology has collided with neuronal cell biology to produce a more integrated understanding of how these remarkable highly differentiated cells utilize common eukaryotic cellular machinery to decode, integrate and propagate signals in the nervous system. The present article gives a very brief and personal overview of the organelles and trafficking machinery of neuronal dendrites and their role in dendritic and synaptic plasticity.

scholarly journals Unfathomed Nanomessages to the Heart: Translational Implications of Stem Cell-Derived, Progenitor Cell Exosomes in Cardiac Repair and Regeneration

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1811
Author(s):  
Charan Thej ◽  
Raj Kishore
Keyword(s):  
Cardiovascular Diseases ◽  
Progenitor Cells ◽  
Cardiac Fibroblasts ◽  
Cell Communication ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Cardiac Cells ◽  
The Body ◽  
Target Cells

Exosomes formed from the endosomal membranes at the lipid microdomains of multivesicular bodies (MVBs) have become crucial structures responsible for cell communication. This paracrine communication system between a myriad of cell types is essential for maintaining homeostasis and influencing various biological functions in immune, vasculogenic, and regenerative cell types in multiple organs in the body, including, but not limited to, cardiac cells and tissues. Characteristically, exosomes are identifiable by common proteins that participate in their biogenesis; however, many different proteins, mRNA, miRNAs, and lipids, have been identified that mediate intercellular communication and elicit multiple functions in other target cells. Although our understanding of exosomes is still limited, the last decade has seen a steep surge in translational studies involving the treatment of cardiovascular diseases with cell-free exosome fractions from cardiomyocytes (CMs), cardiosphere-derived cells (CDCs), endothelial cells (ECs), mesenchymal stromal cells (MSCs), or their combinations. However, most primary cells are difficult to culture in vitro and to generate sufficient exosomes to treat cardiac ischemia or promote cardiac regeneration effectively. Pluripotent stem cells (PSCs) offer the possibility of an unlimited supply of either committed or terminally differentiated cells and their exosomes for treating cardiovascular diseases (CVDs). This review discusses the promising prospects of treating CVDs using exosomes from cardiac progenitor cells (CPCs), endothelial progenitor cells (EPCs), MSCs, and cardiac fibroblasts derived from PSCs.

Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1

Development ◽  
1997 ◽  
Vol 124 (16) ◽  
pp. 3177-3184 ◽  
Author(s):  
P.A. Wilson ◽  
G. Lagna ◽  
A. Suzuki ◽  
A. Hemmati-Brivanlou
Keyword(s):  
Cellular Response ◽  
Organizer Region ◽  
Cell Communication ◽  
Cell Types ◽  
Wing Disc ◽  
Bmp Signaling ◽  
Cell Fates ◽  
Morphogenetic Protein ◽  
Low Concentrations ◽  
Drosophila Protein

Morphogens are thought to establish pattern in early embryos by specifying several cell fates along a gradient of concentration; a well-studied example is the Drosophila protein decapentaplegic (DPP) acting in the wing disc. Recent work has established that bone morphogenetic protein 4 (BMP4), the vertebrate homologue of DPP, controls the fundamental choice between neural and epidermal fates in the vertebrate ectoderm, under the control of antagonists secreted by the organizer region of the mesoderm. We now show that BMP4 can act as a morphogen, evoking distinct responses in Xenopus ectodermal cells at high and low concentrations, in a pattern consistent with the positions of the corresponding cell types in the embryo. Moreover, this complex cellular response to extracellular BMP4 concentration does not require subsequent cell-cell communication and is thus direct, as required of a classical morphogen. We also show that the same series of cell types--epidermis, cement gland and neural tissue--can be produced by progressively inhibiting endogenous BMP signaling with specific antagonists, including the organizer factor noggin. Finally, expression of increasing doses of the signal transduction molecule Smad1 accurately reproduces the response to BMP4 protein. Since Smads have been shown to act in the nucleus, this finding implies a direct translation of extracellular morphogen concentration into transcription factor activity. We propose that a graded distribution of BMP activity controls the specification of several cell types in the gastrula ectoderm and that this extracellular gradient acts by establishing an intracellular and then nuclear gradient of Smad activity.

scholarly journals The hepatocyte clock and feeding control chronophysiology of multiple liver cell types

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. 1388-1394 ◽  
Author(s):  
Dongyin Guan ◽  
Ying Xiong ◽  
Trang Minh Trinh ◽  
Yang Xiao ◽  
Wenxiang Hu ◽  
...  
Keyword(s):  
De Novo ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
De Novo Lipogenesis ◽  
Diurnal Rhythms ◽  
Molecular Clocks ◽  
Peripheral Clocks ◽  
Multiple Cell ◽  
Feeding Control

Most cells of the body contain molecular clocks, but the requirement of peripheral clocks for rhythmicity and their effects on physiology are not well understood. We show that deletion of core clock components REV-ERBα and REV-ERBβ in adult mouse hepatocytes disrupts diurnal rhythms of a subset of liver genes and alters the diurnal rhythm of de novo lipogenesis. Liver function is also influenced by nonhepatocytic cells, and the loss of hepatocyte REV-ERBs remodels the rhythmic transcriptomes and metabolomes of multiple cell types within the liver. Finally, alteration of food availability demonstrates the hierarchy of the cell-intrinsic hepatocyte clock mechanism and the feeding environment. Together, these studies reveal previously unsuspected roles of the hepatocyte clock in the physiological coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.

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