CELLULAR FEEDBACK NETWORKS AND THEIR RESILIENCE AGAINST MUTATIONS

2021 ◽  
pp. 1-50
Author(s):  
LORA D. BAILEY ◽  
NATALIA L. KOMAROVA
Keyword(s):  
Cell Fate ◽  
Feedback Loops ◽  
Wild Type ◽  
Feedback Parameter ◽  
Cell Fate Decisions ◽  
Slowing Down ◽  
Unlimited Growth ◽  
Type Population ◽  
Control Feedback ◽  
Feedback Networks

Many tissues undergo a steady turnover, where cell divisions are on average balanced with cell deaths. Cell fate decisions such as stem cell (SC) differentiations, proliferations, or differentiated cell (DC) deaths, may be controlled by cell populations through cell-to-cell signaling. Here, we examine a class of mathematical models of turnover in SC lineages to understand engineering design principles of control (feedback) loops, that may operate in such systems. By using ordinary differential equations that describe the co-dynamics of SCs and DCs, we study the effect of different types of mutations that interfere with feedback present within cellular networks. For instance, we find that mutants that do not participate in feedback are less dangerous in the sense that they will not rise from low numbers, whereas mutants that do not respond to feedback signals could rise and replace the wild-type population. Additionally, we asked if different feedback networks can have different degrees of resilience against such mutations. We found that all minimal networks, that is networks consisting of exactly one feedback loop that is sufficient for homeostatic stability of the wild-type population, are equally vulnerable. Mutants with a weakened/eliminated feedback parameter might expand from lower numbers and either enter unlimited growth or reach an equilibrium with an increased number of SCs and DCs. Therefore, from an evolutionary viewpoint, it appears advantageous to combine feedback loops, creating redundant feedback networks. Interestingly, from an engineering prospective, not all such redundant systems are equally resilient. For some of them, any mutation that weakens/eliminates one of the loops will lead to a population growth of SCs. For others, the population of SCs can actually shrink as a result of “cutting” one of the loops, thus slowing down further unwanted transformations.

scholarly journals Active elimination of intestinal cells drives oncogenic growth in organoids

2020 ◽  
Author(s):  
Ana Krotenberg Garcia ◽  
Arianna Fumagalli ◽  
Huy Quang Le ◽  
Owen J. Sansom ◽  
Jacco van Rheenen ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Crucial Role ◽  
Intestinal Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Cell Competition ◽  
Type Population

AbstractCompetitive cell-interactions play a crucial role in quality control during development and homeostasis. Here we show that cancer cells use such interactions to actively eliminate wild-type intestine cells in enteroid monolayers and organoids. This apoptosis-dependent process boosts proliferation of intestinal cancer cells. The remaining wild-type population activates markers of primitive epithelia and transits to a fetal-like state. Prevention of this cell fate transition avoids elimination of wild-type cells and, importantly, limits the proliferation of cancer cells. JNK signalling is activated in competing cells and is required for cell fate change and elimination of wild-type cells. Thus, cell competition drives growth of cancer cells by active out-competition of wild-type cells through forced cell death and cell fate change in a JNK dependent manner.

scholarly journals The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination

Blood ◽  
2022 ◽  
Author(s):  
Celine Overbeeke ◽  
Tamar Tak ◽  
Leendert Koenderman
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
Continuous Model ◽  
Feedback Loops ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cellular Kinetics ◽  
Negative Feedback Loops ◽  
Proliferation And Differentiation ◽  
Mature Neutrophil

Neutrophils are the most abundant white blood cell, and differentiate in homeostasis in the bone marrow from hematopoietic stem cells (HSCs) via multiple intermediate progenitor cells into mature cells that enter the circulation. Recent findings support a continuous model of differentiation in the bone marrow of heterogeneous HSCs and progenitor populations. Cell fate decisions both at the level of proliferation and differentiation are enforced through expression of lineage-determining transcription factors (LDTFs) and their interactions, that are influenced by both intrinsic (intracellular) as well as extrinsic (extracellular) mechanisms. Neutrophil homeostasis is subjected to positive feedback loops, stemming from the gut microbiome, as well as negative feedback loops resulting from the clearance of apoptotic neutrophils by mature macrophages. Finally, the cellular kinetics regarding the replenishing of the mature neutrophil pool is discussed in light of recent, contradictory data.

Promoting notochord fate and repressing muscle development in zebrafish axial mesoderm

Development ◽  
1998 ◽  
Vol 125 (8) ◽  
pp. 1397-1406 ◽  
Author(s):  
S.L. Amacher ◽  
C.B. Kimmel
Keyword(s):  
Cell Fate ◽  
Double Mutant ◽  
Muscle Development ◽  
Genetic Interaction ◽  
Embryonic Cells ◽  
Wild Type ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Muscle Genes ◽  
Midline Cells

Cell fate decisions in early embryonic cells are controlled by interactions among developmental regulatory genes. Zebrafish floating head mutants lack a notochord; instead, muscle forms under the neural tube. As shown previously, axial mesoderm in floating head mutant gastrulae fails to maintain expression of notochord genes and instead expresses muscle genes. Zebrafish spadetail mutant gastrulae have a nearly opposite phenotype; notochord markers are expressed in a wider domain than in wild-type embryos and muscle marker expression is absent. We examined whether these two phenotypes revealed an antagonistic genetic interaction by constructing the double mutant. Muscle does not form in the spadetail;floating head double mutant midline, indicating that spadetail function is required for floating head mutant axial mesoderm to transfate to muscle. Instead, the midline of spadetail;floating head double mutants is greatly restored compared to that of floating head mutants; the floor plate is almost complete and an anterior notochord develops. In addition, we find that floating head mutant cells can make both anterior and posterior notochord when transplanted into a wild-type host, showing that enviromental signals can override the predisposition of floating head mutant midline cells to make muscle. Taken together, these results suggest that repression of spadetail function by floating head is critical to promote notochord fate and prevent midline muscle development, and that cells can be recruited to the notochord by environmental signals.

scholarly journals Expression of an activated rasD gene changes cell fate decisions during Dictyostelium development.

1997 ◽  
Vol 8 (2) ◽  
pp. 303-312 ◽  
Author(s):  
S A Louis ◽  
G B Spiegelman ◽  
G Weeks
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Cell Mass ◽  
Cell Formation ◽  
Specific Gene ◽  
Wild Type ◽  
Multicellular Development ◽  
Cell Fate Decisions ◽  
Prespore Cell

It has been previously demonstrated that the expression of an activated rasD gene in wild-type Dictyostelium cells results in formation of aggregates with multitips, instead of the normal single tips, and a block in further development. In an attempt to better understand the role of activated RasD development, we examined cell-type-specific gene expression in a strain stably expressing high levels of RasD[G12T]. We found that the expression of prestalk cell-specific genes ecmA and tagB was markedly enhanced, whereas the expression of the prespore cell-specific gene cotC was reduced to very low levels. When the fate of cells in the multitipped aggregate was monitored with an ecmA/lacZ fusion, it appeared that most of the cells eventually adopted prestalk gene expression characteristics. When mixtures of the [G12T]rasD cells and Ax3 cells were induced to differentiate, chimeric pseudoplasmodia were not formed. Thus, although the [G12T]rasD transformant had a marked propensity to form prestalk cells, it could not supply the prestalk cell population when mixed with wild-type cells. Both stalk and spore cell formation occurred in low cell density monolayers of the [G12T]rasD strain, suggesting that at least part of the inhibition of stalk and spore formation during multicellular development involved inhibitory cell interactions within the cell mass. Models for the possible role of rasD in development are discussed.

scholarly journals Oxygen-generated spatial distribution of cell population links to p53 status

2019 ◽  
Author(s):  
Shashank Taxak ◽  
Uttam Pati
Keyword(s):  
Spatial Distribution ◽  
Cell Fate ◽  
Cell Population ◽  
Oxygen Sensor ◽  
Dynamic State ◽  
Specific Cell ◽  
Wild Type ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Wild Type P53

ABSTRACTLow oxygen induces wild type p53 inactivation and selects for mutant-like p53 phenotypes for aggressive tumor growth. Recently, we have shown wild type p53 as a cellular oxygen-sensor that operates in switch-like fashion to transform its characters of a tumor suppressor or promoter in a gradient of hypoxia. However, it is unclear how hypoxic tumors select for wild type p53 phenotypes for oxygen-sensitive responses. Here, we show that oxygen-generated spatial distribution of the cell population induces p53 phenotype-specific survival or death. We have found that a dynamic state of spatial scatters or clustering patterns of cell populations favor the survival of wild type more than the mutant phenotypes in a wide range of oxygen fluctuation by affecting p53 subcellular localization. Our results demonstrate how spatial distribution could function to establish wild type p53-mediated oxygen sensing and cell fate decisions in a cell population with heterogeneous p53 allele status. We anticipate that such behavior of cells in a gradient of oxygen can be utilized by the hypoxic tumors to maintain distinct p53 alleles and determine the release and metastasis of single or clustered circulating tumor cells (CTCs).Summary sentenceOxygen variation results in p53 phenotype-specific cell fate via the spatial distribution pattern of the cell population

Altered epidermal growth factor-like sequences provide evidence for a role of Notch as a receptor in cell fate decisions

Development ◽  
1993 ◽  
Vol 117 (3) ◽  
pp. 1113-1123 ◽  
Author(s):  
P. Heitzler ◽  
P. Simpson
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Fate ◽  
Cell Interactions ◽  
Signalling Pathway ◽  
Neural Precursor ◽  
Wild Type ◽  
Cell Fate Decisions ◽  
Epidermal Growth

In Drosophila each neural precursor is chosen from a group of cells through cell interactions mediated by Notch and Delta which may function as receptor and ligand (signal), respectively, in a lateral signalling pathway. The cells of a group are equipotential and express both Notch and Delta. Hyperactive mutant Notch molecules, (Abruptex), probably have an enhanced affinity for the ligand. When adjacent to wild-type cells, cells bearing the Abruptex proteins are unable to produce the signal. It is suggested that in addition to the binding of Notch molecules on one cell to the Delta molecules of opposing cells, the Notch and Delta proteins on the surface of the same cell may interact. Binding between a cell's own Notch and Delta molecules would alter the availability of these proteins to interact with their counterparts on adjacent cells.

scholarly journals Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL

2011 ◽  
Vol 208 (4) ◽  
pp. 663-675 ◽  
Author(s):  
Xiaoyu Li ◽  
Takaomi Sanda ◽  
A. Thomas Look ◽  
Carl D. Novina ◽  
Harald von Boehmer
Keyword(s):  
Tumor Suppressor ◽  
Cell Fate ◽  
Lymphoblastic Leukemia ◽  
Wild Type ◽  
Critical Determinant ◽  
Cell Fate Decisions ◽  
Genes Encoding ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway ◽  
Notch1 Mutations

The NOTCH1 signaling pathway is a critical determinant of cell fate decisions and drives oncogenesis through mechanisms that are incompletely understood. Using an established mouse model of T cell acute lymphoblastic leukemia (T-ALL), here we report that induction of intracellular Notch1 (ICN1) leads to repression of miR-451 and miR-709. ICN1 decreases expression of these miRNAs by inducing degradation of the E2a tumor suppressor, which transcriptionally activates the genes encoding miR-451 and miR-709. Both miR-451 and miR-709 directly repress Myc expression. In addition, miR-709 directly represses expression of the Akt and Ras-GRF1 oncogenes. We also show that repression of miR-451 and miR-709 expression is required for initiation and maintenance of mouse T-ALL. miR-451 but not miR-709 is conserved in humans, and human T-ALLs with activating NOTCH1 mutations have decreased miR-451 and increased MYC levels compared with T-ALLs with wild-type NOTCH1. Thus, miR-451 and miR-709 function as potent suppressors of oncogenesis in NOTCH1-induced mouse T-ALL, and miR-451 influences MYC expression in human T-ALL bearing NOTCH1 mutations.

scholarly journals Coregulation of anterior and posterior mesendodermal development by a hairy-related transcriptional repressor

2000 ◽  
Vol 14 (13) ◽  
pp. 1664-1677 ◽  
Author(s):  
Laure Bally-Cuif ◽  
Carole Goutel ◽  
Marion Wassef ◽  
Wolfgang Wurst ◽  
Frédéric Rosa
Keyword(s):  
Cell Fate ◽  
Critical Role ◽  
Transcriptional Repressor ◽  
Cell Interaction ◽  
Wild Type ◽  
Cell Fate Decisions ◽  
Interaction Processes ◽  
Mutant Forms ◽  
Local Release ◽  
Enhancer Of Split

During embryonic development in vertebrates, the endoderm becomes patterned along the anteroposterior axis to produce distinct derivatives. How this regulation is controlled is not well understood. We report that the zebrafish hairy/enhancer of split [E(spl)]-related gene her5 plays a critical role in this process. At gastrulation, following endoderm induction and further cell interaction processes including a local release of Notch/Delta signaling, her5 expression is progressively excluded from the presumptive anterior- and posteriormost mesendodermal territories to become restricted to an adjacent subpopulation of dorsal endodermal precursors. Ectopic misexpressions of wild-type and mutant forms of her5 reveal that her5functions primarily within the endodermal/endmost mesendodermal germ layer to inhibit cell participation to the endmost-fated mesendoderm. In this process, her5 acts as an active transcriptional repressor. These features are strikingly reminiscent of the function of Drosophila Hairy/E(spl) factors in cell fate decisions. Our results provide the first model for vertebrate endoderm patterning where an early regulatory step at gastrulation, mediated by her5 controls cell contribution jointly to the anterior- and posteriormost mesendodermal regions.

C/EBPβ (CCAAT/Enhancer Binding Protein) Controls Cell Fate Determination during Mammary Gland Development

2000 ◽  
Vol 14 (3) ◽  
pp. 359-368 ◽  
Author(s):  
Tiffany N. Seagroves ◽  
John P. Lydon ◽  
Russell C. Hovey ◽  
Barbara K. Vonderhaar ◽  
Jeffrey M. Rosen
Keyword(s):  
Mammary Gland ◽  
Cell Fate ◽  
Binding Protein ◽  
Mammary Glands ◽  
Mammary Development ◽  
Mrna Levels ◽  
Wild Type ◽  
Cell Fate Decisions ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

Abstract Deletion of the transcription factor CCAAT/enhancer binding protein (C/EBP)β results in a severe inhibition of lobuloalveolar development in the mouse mammary gland. Because progesterone receptor (PR) is requisite for alveolar development, the expression of PR was investigated in C/EBPβ−/− mice. Unexpectedly, the number of PR-positive cells, as well as the levels of PR mRNA, were elevated 3-fold in the mammary glands of C/EBPβ−/− mice. Furthermore, in contrast to wild-type nulliparous mice, in which PR distribution shifted from a uniform to nonuniform pattern between 8–12 weeks of age, C/EBPβ−/− mice exhibited uniform PR distribution throughout all stages of mammary development analyzed. No change in C/EBPβ mRNA levels was observed in the mammary glands of PR−/− mice, suggesting that PR acts in a pathway either in parallel to or downstream of C/EBPβ. The overexpression and disrupted cellular distribution of PR in C/EBPβ−/− mice were coincident with a striking 10-fold decrease in cell proliferation after acute steroid hormone treatment, assayed by incorporation of bromodeoxyuridine. In wild-type mice, PR and bromodeoxyuridine-positive cells were adjacent to each other and rarely colocalized. No differences in the level or pattern of PR expression were observed in the uterus, suggesting that C/EBPβ influences PR in a mam-mary-specific fashion. Together, these data suggest that C/EBPβ may control cell fate decisions in the mammary gland through the appropriate temporal and spatial expression of molecular markers, such as PR, that induce the proliferation of alveolar progenitor cells via juxtacrine mechanisms.

Abstract 3445: Notch1 Represses Bmp-Dependent Aortic Valve Calcification in a Cell-Autonomous Manner

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Vishal Nigam ◽  
Deepak Srivastava
Keyword(s):  
Bone Marrow ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Cell Fate ◽  
Developed Countries ◽  
Wild Type ◽  
Aortic Valve Calcification ◽  
Calcific Aortic Stenosis ◽  
Valve Calcification ◽  
Cell Fate Decisions

Calcific aortic stenosis is the third leading cause of adult heart disease and the most common form of acquired valvular disease in developed countries. However, the molecular pathways leading to calcification are poorly understood. We recently reported two families in which heterozygous mutations in NOTCH1 that resulted in premature stop codons caused bicuspid aortic valve and severe calcification of the aortic valve. Notch1 is a part of a highly conserved signaling pathway involved in cell fate decisions, cell differentiation, and cardiac valve formation. We found that mice heterozygous-null for Notch1 had over four-fold more aortic valve calcification compared to age and sex matched littermates (p<0.03). To determine what cell type is involved in the Notch1 related calcification, Notch1+/− bone-marrow was transplanted into wild-type mice. Six months after transplant, there was no difference in the amount of aortic valve calcification between the recipients of Notch1+/− bone-marrow versus recipients of control bone-marrow. In contrast, cultured sheep aortic valve interstitial cells (AVICs) treated with a chemical inhibitor of Notch signaling developed over five-fold more calcification (p<0.03). We found that expression of Bmp2, which has been implicated in human aortic valve disease, was 3-fold higher in aortic valve leaflets of Notch1+/− mice compared to wild type littermates (p<0.02). Furthermore, AVICs treated with the Notch inhibitor had increased Bmp2 protein levels and siRNA-mediated knock-down of Bmp2 expression in the AVICs blocked the calcification process induced by Notch inhibition. These findings suggest that Notch1 signaling within aortic valve cells is required for repression of Bmp2-dependent calcification pathways and may provide novel approaches to inhibit the progression of calcific aortic stenosis.

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