Cells change their sensitivity to an EGF morphogen gradient to control EGF-induced gene expression

Zon, Jeroen S. van; Kienle, Simone; Huelsz-Prince, Guizela; Barkoulas, Michalis; Oudenaarden, Alexander van

doi:10.1038/ncomms8053

Cited by 11 publications

(16 citation statements)

References 43 publications

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“…In contrast, the AC does not migrate during the alignment process, yet represents the source of the VPC migration signal, in addition to its role in vulval induction. Already from the mid-L2 stage, the LIN-3 signal from the AC starts inducing a higher expression in P6.p of transcriptional reporters of Ras pathway activity, such as egl-17 or Delta genes, (Braendle and Félix, 2008;Fisher et al, 2007;Milloz et al, 2008;van Zon et al, 2015). Regardless of whether the induction and migration signals are encoded by the same molecules, this provides a positive feedback loop whereby the most induced VPC is also that most attracted to the inducing AC in the late L2 stage (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…Early L3 animals were placed on RNAi plates, and AC-VPC alignment was measured in the F1 generation at the early L3 stage. Construction of RNAi clones for lin-12 and apx-1 have been described previously (Barkoulas et al, 2013;van Zon et al, 2015). RNAi knock-down was confirmed as treated animals of the same experiments showed vulval hypoinduction at the L4 stage, consistent with reduced Delta/Notch signaling activity.…”

Section: Statistical Analyses and Graphical Representationsmentioning

confidence: 97%

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Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction

Grimbert

Tietze

Barkoulas

et al. 2016

Developmental Biology

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How cells coordinate their spatial positioning through intercellular signaling events is poorly understood. Here we address this topic using Caenorhabditis elegans vulval patterning during which hypodermal vulval precursor cells (VPCs) adopt distinct cell fates determined by their relative positions to the gonadal anchor cell (AC). LIN-3/EGF signaling by the AC induces the central VPC, P6.p, to adopt a 1° vulval fate. Exact alignment of AC and VPCs is thus critical for correct fate patterning, yet, as we show here, the initial AC-VPC positioning is both highly variable and asymmetric among individuals, with AC and P6.p only becoming aligned at the early L3 stage. Cell ablations and mutant analysis indicate that VPCs, most prominently 1° cells, move towards the AC. We identify AC-released LIN-3/EGF as a major attractive signal, which therefore plays a dual role in vulval patterning (cell alignment and fate induction). Additionally, compromising Wnt pathway components also induces AC-VPC alignment errors, with loss of posterior Wnt signaling increasing stochastic vulval centering on P5.p. Our results illustrate how intercellular signaling reduces initial spatial variability in cell positioning to generate reproducible interactions across tissues.

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Section: Discussionmentioning

confidence: 92%

Section: Statistical Analyses and Graphical Representationsmentioning

confidence: 97%

Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction

Grimbert

Tietze

Barkoulas

et al. 2016

Developmental Biology

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“…In addition, ultrasensitivity can increase the robustness of bistable responses141516 and can stabilise biological oscillations17181920212223242526. Finally, ultrasensitivity has been shown to play a major role in converting spatial gradients into sharp boundaries in morphogenesis and developmental patterning27282930313233. In the latter context, our previous work showed that steeper dose-response functions better supported Turing pattern formation in a theoretical developmental model28.…”

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confidence: 98%

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis

Senthivel

Sturrock

Piedrafita

et al. 2016

Sci Rep

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Nonlinear responses to signals are widespread natural phenomena that affect various cellular processes. Nonlinearity can be a desirable characteristic for engineering living organisms because it can lead to more switch-like responses, similar to those underlying the wiring in electronics. Steeper functions are described as ultrasensitive, and can be applied in synthetic biology by using various techniques including receptor decoys, multiple co-operative binding sites, and sequential positive feedbacks. Here, we explore the inherent non-linearity of a biological signaling system to identify functions that can potentially be exploited using cell genome engineering. For this, we performed genome-wide transcription profiling to identify genes with ultrasensitive response functions to Hepatocyte Growth Factor (HGF). We identified 3,527 genes that react to increasing concentrations of HGF, in Madin-Darby canine kidney (MDCK) cells, grown as cysts in 3D collagen cell culture. By fitting a generic Hill function to the dose-responses of these genes we obtained a measure of the ultrasensitivity of HGF-responsive genes, identifying a subset with higher apparent Hill coefficients (e.g. MMP1, TIMP1, SNORD75, SNORD86 and ERRFI1). The regulatory regions of these genes are potential candidates for future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signalling.

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“…4f). However, we have previously measured the lag-2 mRNA degradation rate directly in P6.p, a cell adjacent to the Z1.ppp/Z4.aaa cells, at roughly the same developmental stage as the AC/VU decision [34]. We used this measured rate in P6.p, , as an approximation.…”

Section: Birth Order Biases Cell Fate Outcome For Sufficiently Large mentioning

confidence: 99%

“…We choose parameter values as follows: we based the lag-2 mRNA degradation rate on direct measurements we performed in another cell (P6.p) at a similar stage of development [34]. The mother and daughter cell specific-parameters were obtained by fitting the experimentally observed lag-2 mRNA distribution ( Fig.…”

Section: Simulation and Parametersmentioning

confidence: 99%

Random birth order and bursty Notch ligand expression drive the stochastic AC/VU cell fate decision inC. elegans

Gritti

Kienle

Kroll

et al. 2019

Preprint

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Cells in developing organisms must robustly assume the correct fate in order to fulfill their specific function. At the same time, cells are strongly affected by molecular fluctuations, i.e. 'noise', leading to inherent variability in individual cells. During development, some cells are thought to exploit such molecular noise to drive stochastic cell fate decisions, with cells randomly picking one cell fate out of several possible ones. Yet, how molecular noise drives such decisions is an open question. We address this question using a novel quantitative approach to study one of the best-understood stochastic cell fate decisions: the AC/VU decision in C. elegans gonad development. Here, two initially equivalent cells, Z1.ppp and Z4.aaa, interact, so that one cell becomes the anchor cell (AC) and the other a ventral uterine precursor cell (VU). It is thought that the symmetry is broken when small molecular fluctuations are amplified into cell fate by positive feedback loops in the Notch signaling pathway. To identify the noise sources that drive the AC/VU decision, we used a novel time-lapse microscopy approach to follow expression dynamics in live animals and single molecule FISH to quantify gene expression with single mRNA resolution. We found not only that random Z1.ppp/Z4.aaa birth order biased the decision outcome, with the first-born cell typically assuming VU fate, but that the strength of this bias and the speed of the decision decreased as the two cells were born closer together in time. Moreover, we find that the Notch ligand lag-2/Delta exhibited strongly stochastic expression already in the two mother cells, Z1.pp/Z4.aa. Combining experiments with mathematical models, we showed that the resulting asymmetry in lag-2/Delta levels inherited by the daughter cells, Z1.ppp/Z4.aaa, stochastic symmetry breaking when both cells are born at similar times. Together, our results suggest that two independent noise sources, birth order and stochastic lag-2/Delta expression, are exploited to amplify noise into cell fate in a manner that ensures a robust decision.

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Cells change their sensitivity to an EGF morphogen gradient to control EGF-induced gene expression

Cited by 11 publications

References 43 publications

Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction

Anchor cell signaling and vulval precursor cell positioning establish a reproducible spatial context during C. elegans vulval induction

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis

Random birth order and bursty Notch ligand expression drive the stochastic AC/VU cell fate decision inC. elegans

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