A Network of Broadly Expressed HLH Genes Regulates Tissue-Specific Cell Fates

Bhattacharya, Abhishek; Baker, Nicholas E.

doi:10.1016/j.cell.2011.08.055

Cited by 79 publications

(165 citation statements)

References 106 publications

(85 reference statements)

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“…For example, the conserved regulatory network that controls cell differentiation in Drosophila consists of molecular mechanisms similar to those of the GAL circuit, including molecular sequestration and multiple feedback loops that implement a switch-like developmental program (39,40). Activation of this cell-differentiation circuit relies on molecular titration of a repressor, Extramacrochaetae by the activators Daughterless (Da) and Achaete-Scute complex (As-c).…”

Section: Discussionmentioning

confidence: 99%

Synergistic dual positive feedback loops established by molecular sequestration generate robust bimodal response

Venturelli

El-Samad

Murray

2012

Proc. Natl. Acad. Sci. U.S.A.

115

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Feedback loops are ubiquitous features of biological networks and can produce significant phenotypic heterogeneity, including a bimodal distribution of gene expression across an isogenic cell population. In this work, a combination of experiments and computational modeling was used to explore the roles of multiple feedback loops in the bimodal, switch-like response of the Saccharomyces cerevisiae galactose regulatory network. Here, we show that bistability underlies the observed bimodality, as opposed to stochastic effects, and that two unique positive feedback loops established by Gal1p and Gal3p, which both regulate network activity by molecular sequestration of Gal80p, induce this bimodality. Indeed, systematically scanning through different single and multiple feedback loop knockouts, we demonstrate that there is always a concentration regime that preserves the system's bimodality, except for the double deletion of GAL1 and the GAL3 feedback loop, which exhibits a graded response for all conditions tested. The constitutive production rates of Gal1p and Gal3p operate as bifurcation parameters because variations in these rates can also abolish the system's bimodal response. Our model indicates that this second loss of bistability ensues from the inactivation of the remaining feedback loop by the overexpressed regulatory component. More broadly, we show that the sequestration binding affinity is a critical parameter that can tune the range of conditions for bistability in a circuit with positive feedback established by molecular sequestration. In this system, two positive feedback loops can significantly enhance the region of bistability and the dynamic response time.gene-regulatory network | phenotypic variation | ultrasensitivity

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Section: Discussionmentioning

confidence: 99%

Synergistic dual positive feedback loops established by molecular sequestration generate robust bimodal response

Venturelli

El-Samad

Murray

2012

Proc. Natl. Acad. Sci. U.S.A.

115

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“…S2). We focused our attention on Da because flp-out overexpression clones display a severe undergrowth phenotype (Bhattacharya and Baker, 2011;AndradeZapata and Baonza, 2014), which is the expected phenotype if the sequestration of Da by Emc is required to promote tissue growth. We conducted a directed yeast two-hybrid assay to assess the strength of the interaction between Emc and Da, and find that it is equivalent to our medium/strong positive control colonies (Fig.…”

Section: Emc Functions Downstream Of Notch-induced Proliferation In Tmentioning

confidence: 99%

Inhibition of Daughterless by Extramacrochaetae mediates Notch-induced cell proliferation

Spratford

Kumar

2015

Development

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During development, the rate of cell proliferation must be constantly monitored so that an individual tissue achieves its correct size. Mutations in genes that normally promote tissue growth often result in undersized, disorganized and non-functional organs. However, mutations in genes that encode growth inhibitors can trigger the onset of tumorigenesis and cancer. The developing eye of the fruit fly, Drosophila melanogaster, has become a premier model system for studies that are focused on identifying the molecular mechanisms that underpin growth control. Here, we examine the mechanism by which the Notch pathway, a major contributor to growth, promotes cell proliferation in the developing eye. Current models propose that the Notch pathway directly influences cell proliferation by regulating growth-promoting genes such as four-jointed, cyclin D1 and E2f1. Here, we show that, in addition to these mechanisms, some Notch signaling is devoted to blocking the growth-suppressing activity of the bHLH DNA-binding protein Daughterless (Da). We demonstrate that Notch signaling activates the expression of extramacrochaetae (emc), which encodes a helix-loop-helix (HLH) transcription factor. Emc, in turn, then forms a biochemical complex with Da. As Emc lacks a basic DNA-binding domain, the Emc-Da heterodimer cannot bind to and regulate genomic targets. One effect of Da sequestration is to relieve the repression on growth. Here, we present data supporting our model that Notch-induced cell proliferation in the developing eye is mediated in part by the activity of Emc.

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“…There are hints that Da may be involved in furrow progression. 43 It will be important to determine if the apparent slowing and acceleration of the furrow through loss and overexpression da clones is due to changes in Ci 155 levels and Su(fu). And, finally, for a complete understanding of how Emc regulates Hh signaling, it will be important to identify the entire suite of bHLH proteins that are bound and sequestered by Emc within the developing eye.…”

Section: Discussionmentioning

confidence: 99%

“…42 Consistent with this idea is the initiation of precocious neuronal development in clones overexpressing da. 43 It is yet to be determined if the loss or overexpression of da is sufficient to modulate either Ci 155 or Su(fu) levels. In addition, other bHLH proteins may participate in the regulation of the Hh signaling and may be sequestered by Emc.…”

Section: Flymentioning

confidence: 99%