Notch Signaling Cell Fate Control And Signal Integration In Development Pdf
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- An Overview of Notch Signaling in Adult Tissue Renewal and Maintenance
- Notch signaling: cell fate control and signal integration in development.
- Notch-Signaling and Nonmelanoma Skin Cancer: An Ancient Friend, Revisited
- Glioma cell fate decisions mediated by Dll1-Jag1-Fringe in Notch1 signaling pathway
An Overview of Notch Signaling in Adult Tissue Renewal and Maintenance
Louis, Missouri, USA The Notch pathway is a critical mediator of short-range cell-cell communication that is reiteratively used to regulate a diverse array of cellular processes during embryonic development and the renewal and maintenance of adult tissues.
This releases the Notch intracellular domain, which translocates to the nucleus to activate transcription. The Notch pathway is one of several conserved signaling pathways that regulate cell proliferation, cell fate decisions and induction of differentiation during embryonic and postnatal development [ 1 - 4 ].
Notch receptors are large single-pass Type I membrane proteins. Notch receptors are expressed at the plasma membrane as intramolecular heterodimers, held together by non-covalent interactions within the heterodimerization domain HD. The receptors are activated by binding to ligands presented by a neighboring signal-sending cell.
ADAM-mediated shedding of ligand ectodomains has been shown to modulate the strength and timing of Notch pathway activity. Multiple scissile bonds can be cleaved to release different NICD molecules with varying N-terminal residues. Most receptors undergo processing at cleavage site1 S1 by furin-like proteases in the Golgi and are therefore targeted to the cell surface as an intramolecular heterodimer held together by non-covalent interactions between the N- and C-terminal HD regions Fig 1b.
Recent studies using structure-guided deletions of the S1 sites in human Notch1 and Notch2 demonstrated that S1 cleavage is not absolutely required for receptor activation but it can have differential effects on cell surface trafficking [ 10 ], suggesting that this could be a mechanism for regulating availability at the cell surface and thereby, activation potential of different paralogs. The Notch receptor is activated by binding to a ligand presented by a neighboring cell Fig 1b.
The mechanistic details of how ligand binding promotes Notch receptor proteolysis and activation are emerging Fig 1b [ 7 , 9 , 12 ].
Ligand endocytosis is thought to be required for ligand maturation [ 13 - 15 ] and also, after binding to the receptor, to generate sufficient force to produce a conformational change in the NRR [ 5 , 8 , 16 ].
However, other metalloproteases may also play a role in tissues where ADAM10 is not expressed and in disease states. Elevated metalloprotease levels can lead to ligand-independent activation of Notch receptors [ 23 , 24 ]. Interestingly, Notch receptors that are activated in a ligand-independent manner specifically, by calcium chelation [ 25 ], or by T-ALL-associated and other activating mutations that destabilize the NRR [ 26 , 27 ] are no longer mainly dependent on ADAM10 for ectodomain shedding.
The molecular mechanisms underlying this selectivity are still unclear. S2 cleavage is a major regulatory step in the Notch activation process. Early genetic studies demonstrated the requirement of endocytosis in both the signal-sending and signal-receiving cells [ 16 , 31 ]. In the signal-receiving cell, endocytosis could also be contributing to this process [ 9 , 32 ]. Alternatively or in addition, endocytosis might be required for cleavage to occur at least in some contexts [ 33 ].
Moreover, the cellular location where cleavage occurs can influence the precise position of S3 cleavage and as a consequence, modulate the stability of released NICD molecules [ 34 ].
This too can potentially be a point of pathway regulation. Together, they recruit the coactivator Mastermind, and further assemble a transcriptional complex that activates downstream targets Fig 1b [ 2 , 7 , 9 , 35 , 36 ]. Ligand proteolysis can be constitutive and likely depends on the availability of ADAMs. Indeed, activating ADAMs with p-aminophenylmercuric acetate increases ligand cleavage [ 38 ].
Notch receptor binding can also enhance ligand cleavage [ 38 , 39 ]. ADAM-mediated ectodomain shedding of ligands is thought to be important for their downregulation, which helps promote and maintain unidirectional signaling [ 38 , 40 - 42 ] or alleviate cis -inhibition [ 41 , 43 ]. Ligand ectodomain shedding by ADAM appears to be dispensable during T-cell development [ 44 ] but is critical during cortical neurogenesis [ 45 ] and for maintaining the balance between self-renewal and differentiation in muscle satellite cells [ 46 ].
Alternatively, ligand proteolysis could be releasing functional ICD fragments analogous to NICD that could regulate transcription and be involved in ligand back signaling [ 39 , 49 ]. Because most of the studies regarding the functions of released ligand ICD fragments have relied on overexpressed or engineered protein fragments, additional studies will have to address whether such a bidirectional mode of signaling from endogenously expressed and cleaved ligands plays a role in specific contexts in vivo.
The core or canonical pathway is conserved for all Notch receptors and is utilized in most Notch-dependent processes. This direct membrane-to-nucleus signaling mechanism occurs without any signal amplification by secondary messengers, but is regulated by post-translational modifications e.
In a context-dependent manner, these regulatory mechanisms modulate the strength and timing of Notch signals, and ultimately their biological consequences.
The essential function of Notch signaling in development is evident in the early embryonic lethality associated with loss of Notch signaling. Global knockouts of Notch1 or 2 in mice are embryonic lethal mainly due to the early defects in neurons, somites, and vascular integrity both in the embryo and placenta [ 58 - 61 ]. Knockouts of the other key components and modifiers of the Notch signaling pathway also support the view that Notch signaling is dispensable for gastrulation but essential for post-implantation mammalian development, starting at E9 [ 64 ].
PS2 is dispensable for embryogenesis, but the double knockout of PS1 and PS2 is more severe and nearly identical to Notch signaling knockout mice [ 67 ]. Nicastrin- and Aph1a-null mice also exhibit embryonic lethal phenotypes, although Aph1b and c are dispensable for embryogenesis [ 68 - 72 ]. A growing number of studies have begun to investigate the roles of Notch signaling in adult mammals, thanks to the recent advances in inducible Cre-loxP targeting technology, which makes it possible to study both temporal and spatial regulation and functions of Notch signaling in vivo.
It has been demonstrated that Notch signaling is critical in tissue renewal and maintenance in various organs, including but not limited to, the intestine, skin, blood, liver, kidney, nervous system, bone and muscle. Thus, one can easily imagine that acute or chronic disruption of the pathway can lead to various complications in multiple organs.
However, important questions such as how much reduction of Notch signaling can be tolerated in each tissue remain largely unanswered. In addition, Notch signaling functions in a highly context-dependent manner; biological consequences of pathway activation can vary depending on multiple factors, such as cell type, timing, and mode of signaling. Therefore, understanding the role of Notch signaling in each organ is critical for identifying a therapeutic window for GSIs.
In the following sections, we highlight some of the key roles of Notch signaling in actively self-renewing tissues, such as the intestine, hematopoietic system, and skin. In addition, we discuss the potential roles of Notch signaling in cell renewal systems within the brain and muscle, which go through slower turnover. The epithelium of the intestine is one of the most rapidly and dynamically renewed tissues in the adult.
It renews every four to five days, and failure to maintain this homeostasis can lead to death. Mild disruptions can lead to malnutrition, infection, and cancer. Notch signaling has been shown to regulate cell renewal and binary fate decisions in the adult intestine in concert with Wnt signaling, which functions as the master switch that promotes cell proliferation and suppresses differentiation Fig 2a [ 77 - 83 ].
This suggests that Notch signaling regulates binary cell fate decision between these two cell lineages. In a reciprocal experiment, forced expression of NICD in the intestine led to reduction of secretory cells and increased cell proliferation [ 86 ].
These results suggest that there are two roles of Notch signaling in the adult intestine: it promotes proliferation either in the ISC or TA cell compartment, and it regulates binary fate decisions between absorptive and secretory cells. The first role was shown to be Wnt signaling-dependent while the second is independent of Wnt signaling [ 87 ].
In zebrafish, lateral inhibition through Delta-mediated Notch signaling has been implicated to play a role in these binary cell fate decisions [ 88 ]. Notch1 and Notch2 have been shown to function redundantly in the gut [ 84 , 89 ]. Notch signaling is utilized in multiple organs in the adult for cell renewal and tissue maintenance.
They produce transit amplifying TA cells light orange , and differentiate into four types of cells: absorptive enterocyte light blue , secretory goblet green , enteroendocrine blue , and Paneth purple cells. Notch signaling promotes blue arrow proliferation of the adult ISCs and determines binary cell fate decisions between absorptive and secretory cells.
It is still controversial whether Notch signaling regulates proliferation of hematopoietic stem cells HSCs: pink in the adult. Ablation of Notch signaling leads to tumorigenesis through non-cell autonomous effects.
It also leads to secretion of thymic stromal lymphopoietin TSLP , which can eventually lead to atopic dermatitis and asthma in the adult.
Notch signaling could also promote survival and maturation of neurons and modulate neuritogenesis in mature neurons. Asymmetric localization of Notch inhibitor Numb during cell divisions results in two daughter cells: myoblast blue and a myogenic progenitor. Treatment with GSIs promoted goblet cell differentiation and reduced proliferation in adenomas [ 85 ], suggesting that GSIs may also be useful in the treatment of neoplastic diseases in the gut [ 90 ].
Recent in vivo studies using a combination of the GSI compound E, and the glucocorticoid dexamethasone, have successfully improved the anti-leukemic effects in T-ALL while reducing intestinal toxicity, showing that dosage control is feasible [ 94 ]. The hematopoietic system undergoes rapid and robust cell renewal throughout life, and its dysregulation can lead to various hematologic diseases such as anemia, leukemia, and immune disorders.
During embryonic development, hematopoietic stem cells HSCs primitively arise from the yolk sac and aorta-gonad mesonephros, which is followed by its generation in the fetal liver and bone marrow. In adult animals, HSCs primarily reside in the bone marrow, and they can give rise to all hematopoietic cell lineages, including myeloid cells monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes, dendritic cells and lymphoid cells T cells, B cells, natural killer NK cells [ 95 , 96 ].
Notch signaling has been implicated in multiple cell fate decisions during hematopoiesis Fig 2b [ 80 , 97 - 99 ]. A number of loss- and gain-of-function studies of Notch1 in bone marrow progenitors have demonstrated that Notch signaling instructs T cell fate at the expense of B cell fate [ - ].
Importantly, early versions of GSIs inhibited T cell development in mouse fetal thymus organ cultures [ , ]. In follow up studies with human-mouse fetal thymus organ cultures, the GSI DAPT was shown to dose-dependently affect different hematopoietic cell lineage development: T cells required a higher dose of Notch signaling, NK cells were generated with a low dosage of Notch signaling whereas B-cells were generated in the absence of Notch signaling [ ].
T cell lineage commitment was shown to be mediated through Dll4 expressed in thymic epithelial cells, implicating a thymic niche for T cell development [ , ]. It has been further shown that Notch signaling inhibits additional cell fate decisions including myeloid cells and dendritic cells to ensure T cell lineage commitment [ , ]. Notch signaling has also been suggested to regulate HSC renewal Fig 2b , but this is still highly controversial.
Notch1 was shown to be required for generating HSCs during embryonic development [ - ]. In addition, osteoblast-specific expression of parathyroid hormone related protein receptor increased Jagged1 expression, which resulted in HSC expansion, implicating that Jagged1-mediated Notch signaling creates a HSC niche in the bone [ ]. The skin is another organ that goes through robust self-renewal throughout life, and dysfunction in the skin barrier can result in dehydration, infection, or cancer.
As in the gut, adult stem cells can be found in two places in the skin, a proliferative population in the epidermis and the hair bulb, and a quiescent population in the bulge region of the hair follicles [ 73 ]. The epidermis consists of four layers: basal innermost , spinous, granular, and cornified layers, which express different cellular markers. The adult skin epidermal stem cells reside in the basal layer, and as they detach and migrate outward, they commit to terminal differentiation [ , ].
Notch signaling regulates differentiation and proliferation of adult stem cells in the epidermis Fig 2c [ 80 , - ]. However, this view was challenged by a recent study using a multistage chemical skin carcinogenesis paradigm on a chimeric mouse model of Notch deletion in the skin.
Moderate reduction of Notch signaling in the skin can dose-dependently increase the susceptibility to tumorigenesis. While conditional knockout of either Notch2 or 3 alone in the postnatal epidermis exhibited no phenotype, stepwise deletion of Notch paralogs dose-dependently accelerated skin carcinogenesis, suggesting that Notch1, 2 and 3 were not redundant but additive [ ].
Another study has shown that skin barrier defects caused by loss of Notch signaling can induce systemic B-lymphoproliferative disorder in newborn mice through a dose-dependent secretion of thymic stromal lymphopoietin TSLP , which can eventually lead to atopic dermatitis and asthma in adult animals [ , ].
While TSLP can be useful as a biomarker for Notch-mediated skin barrier defects, these results raise the concern that even a moderate reduction of Notch signaling can increase susceptibility to carcinogenesis in the skin and simultaneously add risks of atopic dermatitis and asthma.
Unlike the intestine, blood, or skin where massive cell renewal is continuous throughout life, the vast majority of neurogenesis takes place during embryonic development. Adult neurogenesis occurs in two restricted regions of the brain - in the subgranular zone SGZ of the hippocampus and the subventicular zone SVZ of the lateral ventricle.
Although the functional role of adult neurogenesis is not fully understood, it has been implicated in hippocampus-dependent learning and memory, and neurological disorders such as epilepsy and AD.
Moreover, adult neurogenesis can be enhanced upon injury, exercise, or an enriched environment [ , ]. Notch signaling has classically been shown to play a critical role in the maintenance of neural progenitor identity and the inhibition of neuronal differentiation during early development [ ].
The current view holds that while Notch signaling may inhibit the neural fate in the early developmental stage, it can also instruct or permissively allow fate choices between different subtypes of neural cells in the later stage, serving as a binary switch of cell fate determination [ ]. Emerging evidence also suggests multiple roles for Notch signaling in adult neurogenesis Fig 2d [ 80 , ].
TA cells proliferate rapidly, exit from cell cycle and produce neural progenitor cells NPCs , which migrate from SGZ and SVZ to the granule cell layer or olfactory bulb, respectively, where they mature into neurons. The discrepancy from the previous study may be due to residual signaling by other Notch receptors in the Notch1 knockout mice.
Notch signaling: cell fate control and signal integration in development.
Cell-cell interactions mediated by the Notch signaling pathway occur throughout C. These interactions have major roles in specifying cell fates and in tissue morphogenesis. The network of Notch interactions is linked in part through the Notch-regulated expression of components of the pathway, allowing one interaction to pattern subsequent ones. The Notch signal transduction pathway is highly conserved in animal embryogenesis. The Notch signaling pathway plays a central role in patterning metazoan development, and is used in remarkably diverse cell fate decisions for general review, see Artavanis-Tsakonas et al. Cell interactions mediated by these receptors have been documented throughout embryonic and postembryonic development of C.
The Notch signaling pathway is a highly conserved cell signaling system present in most animals. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium -dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region. Notch signaling promotes proliferative signaling during neurogenesis , and its activity is inhibited by Numb to promote neural differentiation. It plays a major role in the regulation of embryonic development. In , John S.
Wing margin formation in Drosophila requires the Notch receptor and, in the dorsal compartment, one of its ligands, Serrate. We provide evidence that Delta, the other known ligand for Notch, is also essential for this process. Moreover, ectopic Delta expression induces wingless, vestigial, and cut and causes adult wing tissue outgrowth in the dorsal compartment. The effect is mediated by Notch, because loss of Notch activity suppresses Delta-induced ectopic wing outgrowth. Whereas ectopic expression of Notch or the truncated activated Notch induces cut in both dorsal and ventral compartments, ectopic Delta expression induces cut only in the dorsal compartment and ectopic Serrate induces cut only in the ventral compartment. These observations indicate that Notch-expressing cells in a given compartment have different responses to Delta and Serrate. We propose that Delta and Serrate function as compartment-specific signals in the wing disc, to activate Notch and induce downstream genes required for wing formation.
Notch-Signaling and Nonmelanoma Skin Cancer: An Ancient Friend, Revisited
Louis, Missouri, USA The Notch pathway is a critical mediator of short-range cell-cell communication that is reiteratively used to regulate a diverse array of cellular processes during embryonic development and the renewal and maintenance of adult tissues. This releases the Notch intracellular domain, which translocates to the nucleus to activate transcription. The Notch pathway is one of several conserved signaling pathways that regulate cell proliferation, cell fate decisions and induction of differentiation during embryonic and postnatal development [ 1 - 4 ].
Glioma cell fate decisions mediated by Dll1-Jag1-Fringe in Notch1 signaling pathway
Metrics details. The Notch family of proteins plays a vital role in determining cell fates, such as proliferation, differentiation, and apoptosis. It has been shown that Notch1 and its ligands, Dll1 and Jag1, are overexpressed in many glioma cell lines and primary human gliomas. The roles of Notch1 in some cancers have been firmly established, and recent data implicate that it plays important roles in glioma cell fate decisions. This paper focuses on devising a specific theoretical framework that incorporates Dll1, Jag1, and Fringe in Notch1 signaling pathway to explore their functional roles of these proteins in glioma cells in the tumorigenesis and progression of human gliomas, and to study how glioma cell fate decisions are modulated by both trans-activation and cis-inhibition.
The Notch signaling pathway plays an important role in development and physiology. In Drosophila, Notch is activated by its Delta or Serrate ligands, depending in part on the sugar modifications present in its extracellular domain. Besides its O-fucosyltransferase activity, OFUT1 also behaves as a chaperone during Notch synthesis and is able to down regulate Notch by enhancing its endocytosis and degradation. We have reevaluated the roles that O-fucosylation and the synthesis of GDP-fucose play in the regulation of Notch protein stability. The Notch signaling pathway is present from nematodes to humans and carries out fundamental roles in a wide variety of developmental processes Lai, In Drosophila, the intercellular communication mediated by this pathway is performed by the Notch receptor N and its ligands Delta Dl and Serrate Ser ligands. Binding of the ligands to Notch induces its proteolytic cleavage within the juxtamembrane domain, leading to the release of the intracellular domain N ICD.
Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. DOI: Artavanis-Tsakonas and M. Rand and R. Artavanis-Tsakonas , M. Rand , R.
Notch Signaling in Embryology and Cancer pp Cite as. In humans and other species, Notch-signaling is of critical importance for carcinogenesis in several organs, including the skin. Interestingly, Notch-signaling appears to exert opposite roles in skin carcinogenesis as compared to carcinogenesis in other tissues. While the Notch1 receptor Notch1 acts as a proto-oncogene in most tissues, it has been shown that Notch1 deletion in epidermal keratinocytes causes skin carcinogenesis. Recent results indicate that loss of Notch1 is not involved in the initiating event of multistage skin carcinogenesis, but acts as a skin cancer-promoting event.
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