notch signaling cell fate control and signal integration in development pdf

Notch Signaling Cell Fate Control And Signal Integration In Development Pdf

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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.

Notch-Signaling and Nonmelanoma Skin Cancer: An Ancient Friend, Revisited

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.

This paper presents a computational model for Notch1 signaling pathway in glioma cells. Based on the bifurcation analysis of the model, we show that how the glioma cell fate decisions are modulated by both trans-activation and cis-inhibition mediated by the Fringe protein, providing insight into the design and control principles of the Notch signaling system and the gliomas.

This paper presents a computational model for Notch1 signaling pathway in glioma cells based on intertwined dynamics with cis-inhibition and trans-activation involving the proteins Notch1, Dll1, Jag1, and Fringe.

The results show that how the glioma cell fate transitions are performed by the Notch1 signaling. Notch signaling pathway is an evolutionarily conserved cell-cell communication mechanism governing cell fate decisions during cell development.

The Notch inactivation within the same cell is termed as cis-inhibition, which leads to the degradation of both proteins, therefore not generating a signal. The Notch receptor of one cell binds with a Notch ligand of its neighboring cells, i. It has been shown that the trans-activation and cis-inhibition play important roles in cell fate decisions, such as neural fate decisions [ 5 ].

To date, four Notch receptors have been identified Notch in humans, with five canonical ligands including three members of the Delta family Dll1, Dll3, Dll4 and two members of the Serrate family Jag1 and Jag2, homologues of Drosophila Serrate [ 6 ]. At the same time, the family of Fringe-related proteins is a major Notch regulator, which can promote or suppresse Notch signaling, depending on the Notch ligands [ 7 , 8 ]. Of the three mammalian Fringe proteins, it has been shown that only LFng can enhance Notch1 signaling induced by Dll1 and suppress the signaling induced by Jag1 in coculture reporter assays [ 9 ].

It has been also shown that MFng can suppress Jag1 induced signaling through Notch1, while the effects of MFng on Notch1 signaling in response to Dll1 have not been reported [ 10 ]. Given the evolutionary conservation of the Notch pathway, three Fringe proteins in human have also been identified [ 11 ]. The Notch family of receptors consists of heterodimeric transmembrane proteins intimately involved in the determination of cell fate.

Notch signaling can play a positively or negatively role in processes of proliferation, differentiation, and apoptosis, depending on the cell type [ 12 , 13 ]. Dll1 and Jag1 have been found to be up-regulated in cervical cancers [ 16 ].

More recently, it has been shown that the Jag1 intracellular domain can up-regulate the activator protein 1 AP-1 activity [ 17 ], a signaling pathway known to be important in many cancers. To date, it has been shown that Notch1 and its ligands, Dll1 and Jag1, are overexpressed in many glioma cell lines and primary human gliomas. Immuno-histochemistry of a primary human glioma tissue array shows the presence in the nucleus of the Notch1 intracellular domain, indicating Notch1 activation in situ.

Down-regulation of Notch1, Dll1, or Jag1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines [ 18 ]. Glioma is the most common clinical central nervous system malignancies. The patients with glioma have poor effects.

The average survival time is short [ 19 ]. It has been demonstrated that Notch1 mRNA in human brain gliomas and normal brain tissue can be expressed, but the expression in human gliomas was significantly higher than in normal brain tissue, indicating that the expression levels of Notch1 may be associated with human glioma tumorigenesis and development. As for standard therapies, such as chemotherapy, surgery, and radiation, have had limited success in treating patients with high-grade gliomas.

Therefore, Notch1 and its ligands may present novel therapeutic targets in the treatment of gliomas. The purpose of this paper is to present a computational model for Notch1 signaling pathway in glioma cell lines and primary human gliomas based on intertwined dynamics with cis-inhibition and trans-activation involving the proteins Notch1, Dll1, Jag1, and Lunatic Fringe. Mathematical models of Notch signaling, with different levels of sophistication, have been proposed for different organisms for which sufficient knowledge of molecular biology exists.

All these models can produce different results but are not sufficient in several important respects. First, most of the previous models do not include an essential characteristic of Notch signaling, i. Second, even when cis-inhibition is incorporated, its link to glioma cell lines and primary human gliomas and its effects on cell fate decisions have not been well considered [ 23 ].

Most models focus on how Notch signaling plays different roles in various cell fate decisions, but how Fringe affects the fate decisions in glioma cell lines has not been well investigated.

Thus, a new model needs to be developed so as to investigate the combinatorial effects of cis-inhibition, trans-activation, and Fringe regulation on glioma cell fate decisions, their operating mechanisms, and potential implications in the treatment of gliomas. Notch1 signaling pathway is involved in glioma stem cells proliferation and differentiation. It has been shown that Notch1 protein is over expressed in human gliomas [ 19 ]. Notch1 signaling pathway, including the processes of cis-inhibition, trans-activation, and the regulation mediated by Lunatic Fringe is shown in Fig.

It is known that Fringe may play an important role in the treatment of gliomas. System for signal integration in the intracellular and intercellular Notch1 signaling pathway. Notch1, the transmembrane receptor of one cell, binds to Dll1 or Jag1, the transmembrane ligands belonging to the neighboring cell. This trans-interaction leads to the cleavage and release of NICD that regulates the production of the two ligands asymmetrically, i.

Interaction between Notch1 receptor and ligands Dll1 or Jag1 of the same cell cis-interaction leads to the degradation of both the receptor and the ligands.

Glycosylation of Notch1 by Fringe modifies Notch1 to have a higher affinity for binding to Dll1 and a lower affinity for binding to Jag1. Regulation diagram. Notch1 could interact by cis and trans with Jag1 and Dll1 ligands, and in which one of the Fringe-related proteins, Lunatic Fringe LFng , could modulate these interactions. LFng modification of Notch1 enhances trans activation from Dll1 and weakens trans-activation from Jag1 left. LFng modification of Notch1 enhances cis-interactions with Dll1 and weakens cis-interactions with Jag1 right.

For gliomas, most researchers are currently engaged in the study on related factors of Notch signaling pathway [ 7 , 19 ], they pay less attention to the relationship between the related factors in terms of mathematical theory. The model presented here involves several aspects. First, the Notch1 binds to Dll1 or Jag1 with the same affinity when the regulation mediated by Fringe is not incorporated.

Second, when the Fringe regulation on pathway is incorporated, it can increase the Notch1-Dll1 binding affinity and decrease the Notch1-Jag1 binding affinity. We mainly consider the two-cell system, and the system can be extended to the case where each cell has j -neighbors.

The basic model of Notch signaling incorporating the cis-inhibition and trans-activation was previously developed [ 24 ]. Subsequent model by incorporating Jag1 in addition to Delta and the asymmetric effect of NICD which activates Notch and Jag1 but represses Delta was also proposed [ 25 ]. Trans-interaction leads to the release of the NICD signal into the cytoplasm, resulting in subsequent activation of downstream target genes, while cis-interaction leads to the degradation of both proteins, Notch and Delta, therefore no generation of any signal.

N ext , D ext , and J ext represent the amount of protein available for binding from neighboring cells. Glycosylation of Notch1 by Fringe modulates the binding affinity of the two ligands to Notch1. The glycosylated Notch1 has a higher binding affinity for Dll1 but lower affinity to bind to Jag1, compared to the unglycosylated Notch1 [ 6 ].

Thus, to incorporate this mechanism to our model, while representing effective Notch1 in gliomas cell sum of glycosylated and unglycosylated Notch1 , the model can be rewritten as.

Hill functions are used to show the effects of Fringe on cis-inhibition and trans-activation. The standard values of all parameters are listed in Table 1. In the two cell model, the adjacent cell means the other cell. But for the hexagonal cell arrangement, the adjacent cells mean the six immediate neighbors, the sum of the expression levels in adjacent cells is divided by six.

These regulatory processes can be expressed by a set of ordinary differential equations as follows. Several studies have reported abnormal activity of Notch1 in human brain tumors.

But it is still not clear how Notch1 signaling pathway affects the occurrence and maintenance of gliomas. In the following sections, based on bifurcation analysis of the models, we will analyze how Notch1 signaling pathway modulates glioma cell fate decisions. Gliomas may produce neural stem cells which can then differentiate into neurons or glial cells at all stages of tumorigenesis at maturity. Therefore, it could be argued that gliomas produced by cells with different maturity level can show different expression of Notch1 signal cascade of spectrum, which reflects the origin of gliomas [ 26 ].

These expression products can also be used to identify different grades of gliomas, including primary and secondary gliomas. Studies have shown correlation of Notch1 expression and glioma grades [ 27 — 29 ]. Immunohistochemistry of a primary human glioma tissue array shows the presence of the Notch1 intracellular domain in the nucleus, indicating Notch1 activation in situ. Down-regulation of Notch1, Dll1, or Jag1 by RNA interference can induce apoptosis or inhibit proliferation in multiple glioma cell lines.

Notch1 and its ligands may present novel therapeutic targets in the treatment of gliomas [ 18 ]. Preliminary works in laboratory from phage display biopanning on human glioma cells resulted in the isolation of two peptides that share significant homology to regions of Jag1 and Dll1, two Notch1 receptor ligands. These findings suggested the presence of Notch1 on human glioma cells, which was further supported by cDNA microarray data.

All these findings prompt us to study the biological relevance of Notch signaling to the glioma cell fate decisions. We explore the effects of Dll1-Jag1-Fringe on glioma cell fate decisions by analyzing the model 5 - 8. The effect of ligand Jag1 and Fringe is shown in Fig. As we can see from a and b , for the case of no Fringe, when the value of Jag1 becomes more larger, the system changes from twice transitions to only once. The difference between a and c is the value of a on behalf of Fringe existence , which represents the presence of Fringe, but only a small intensity.

Stable steady states almost do not change. When the a value is further increased, the transition becomes only once.

Bifurcation diagrams for the levels of different proteins. The effects of ligand Dll1 and Fringe on the system dynamics are shown in Fig. As we can see from a and b , for the case of no Fringe, when the value of Dll1 becomes more larger, the system changes from twice state transitions to only once.

However, when the Fringe regulation is large enough, we can see that on state transitions occur even when J ext is small enough. Compared with Fig. Bifurcation diagrams. From Figs. It has been experimentally shown that given the expression of Dll1 in primary human gliomas, efficient Dll1 were transfected into six glioma lines and their effects assessed. Dll1 knockdown produced dramatic effects, inducing a spindleshaped morphology initially not shown with subsequent cell death.

Significant decreases in viable cell number were evident in all six glioma cell lines as evaluated by alamarBlue assay. We first evaluate the dynamics of N-D signaling for the two-cell system 13 - Bifurcation diagrams with k t as a control parameter is showed in Fig.

Notch signaling pathway

The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism that is required for embryonic development, cell fate specification, and stem cell maintenance. Discovered and studied initially in Drosophila melanogaster , the Notch pathway is conserved and functionally active throughout the animal kingdom. In this paper, we summarize the biochemical mechanisms of Notch signaling and describe its role in regulating one particular developmental pathway, oogenesis in Drosophila. Utilized by the simplest metazoans through mammals, Notch signaling is an evolutionarily conserved signaling pathway that is required for embryonic development, cell fate specification, and stem cell maintenance [ 1 — 5 ]. Notch signaling selects among preexisting cellular potentials to specify different cell fates and activate different programs through either promoting or suppressing differentiation, proliferation, survival, and apoptosis [ 6 , 7 ]. In humans, mutations in this pathway cause inherited genetic diseases such as Alagille syndrome, spondylocostal dysostosis, Hadju-Cheney syndrome, Tetralogy of Fallot, familial aortic valve disease, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Dysregulation of Notch activity also is associated with T-cell acute lymphatic leukemia and other cancers e.

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.

Notch signaling: cell fate control and signal integration in development.

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.

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. This paper presents a computational model for Notch1 signaling pathway in glioma cells. Based on the bifurcation analysis of the model, we show that how the glioma cell fate decisions are modulated by both trans-activation and cis-inhibition mediated by the Fringe protein, providing insight into the design and control principles of the Notch signaling system and the gliomas.

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.


Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development. Signals exchanged.


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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. Dexter noticed the appearance of a notch in the wings of the fruit fly Drosophila melanogaster. The alleles of the gene were identified in by American evolutionary biologist Thomas Hunt Morgan.

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. Moreover, recent findings underline the importance of multiple other factors, including the microenvironment, for Notch signaling in skin carcinogenesis. It can be speculated that pharmacologic modulation of Notch signaling may be an interesting target for the prevention and therapy of skin cancer.

King , The unicellular ancestry of animal development , Dev Cell , vol. Thakur, H. Ushijima, A. Thakur, A. Krasko et al. Pires-dasilva and R. Sommer , The evolution of signalling pathways in animal development , Nat Rev Genet , vol.

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