Studies of morphogens: keep calm and carry on

Stathopoulos, Angelike; Iber, Dagmar

doi:10.1242/dev.095141

Cited by 40 publications

(19 citation statements)

References 44 publications

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“…This greater challenge is reflected in the scarcity of well-established, generally applicable mechanisms to explain pattern scaling, in comparison with other aspects of biological patterning (Lander, 2011; Stathopoulos and Iber, 2013). Most mechanisms proposed to explain scale invariance rely on the scaling of morphogen gradients.…”

Section: Discussionmentioning

confidence: 99%

Collective Space-Sensing Coordinates Pattern Scaling in Engineered Bacteria

Cao

Ryser

Payne

et al. 2016

Cell

115

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Summary Scale invariance refers to the maintenance of a constant ratio of developing organ size to body size. Though common, its underlying mechanisms remain poorly understood. Here we examined scaling in engineered E. coli that can form self-organized core-ring patterns in colonies. We found that the ring width exhibits perfect scale invariance to the colony size. Our analysis revealed a collective space-sensing mechanism, which entails sequential actions of an integral feedback loop and an incoherent feedforward loop. The integral feedback is implemented by the accumulation of a diffusive chemical produced by a colony. This accumulation, combined with nutrient consumption, sets the timing for ring initiation. The incoherent feedforward is implemented by the opposing effects of the domain size on the rate and duration of ring maturation. This mechanism emphasizes a role of timing control in achieving robust pattern scaling and provides a new perspective in examining the phenomenon in natural systems.

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Section: Discussionmentioning

confidence: 99%

Collective Space-Sensing Coordinates Pattern Scaling in Engineered Bacteria

Cao

Ryser

Payne

et al. 2016

Cell

115

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“…In fact it remains controversial if they even form gradients, and few studies have examined their spatial and temporal dynamics (Stathopoulos & Iber, 2013). The best studied is Bicoid in Drosophila , which clearly forms a gradient of nuclear protein along the anterior–posterior (A–P) axis in the early embryo (Driever & Nusslein-Volhard, 1988a, 1988b; Grimm, Coppey, & Wieschaus, 2010).…”

Section: Challenges For Morphogen Gradient Studiesmentioning

confidence: 99%

Visualizing retinoic acid morphogen gradients

Schilling

Sosnik

Nie

2016

Methods in Cell Biology

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Morphogens were originally defined as secreted signaling molecules that diffuse from local sources to form concentration gradients, which specify multiple cell fates. More recently morphogen gradients have been shown to incorporate a range of mechanisms including short-range signal activation, transcriptional/translational feedback, and temporal windows of target gene induction. Many critical cell–cell signals implicated in both embryonic development and disease, such as Wnt, fibroblast growth factor (Fgf), hedgehog (Hh), transforming growth factor beta (TGFb), and retinoic acid (RA), are thought to act as morphogens, but key information on signal propagation and ligand distribution has been lacking for most. The zebrafish provides unique advantages for genetics and imaging to address gradients during early embryonic stages when morphogens help establish major body axes. This has been particularly informative for RA, where RA response elements (RAREs) driving fluorescent reporters as well as Fluorescence Resonance Energy Transfer (FRET) reporters of receptor binding have provided evidence for gradients, as well as regulatory mechanisms that attenuate noise and enhance gradient robustness in vivo. Here we summarize available tools in zebrafish and discuss their utility for studying dynamic regulation of RA morphogen gradients, through combined experimental and computational approaches.

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“…Although the existence of these gradients is now well established (1), the quantitative details of their functioning (i.e. how small differences in morphogen concentrations are precisely and robustly interpreted into a thresholddependent step-like response) remains largely debated (2).…”

Section: Introductionmentioning

confidence: 99%

3 minutes to precisely measure morphogen concentration

Lucas

Tran

Romero

et al. 2018

Preprint

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Morphogen gradients provide concentration-dependent positional information along polarity axes. Although the dynamics of establishment of these gradients is well described, precision and noise in the downstream activation processes remain elusive. A simple paradigm to address these questions is the Bicoid morphogen gradient that elicits a rapid step-like transcriptional response in young fruit fly embryos. Focusing on the expression of the main Bicoid target, hunchback (hb), at the onset of zygotic transcription, we used the MS2-MCP approach which combines fluorescent labeling of nascent mRNA with live imaging at high spatial and temporal resolution. Removing 36 putative Zelda binding sites unexpectedly present in the original MS2 reporter, we show that the 750 bp of the hb promoter are sufficient to recapitulate endogenous expression at the onset of zygotic transcription. After each mitosis, in the anterior, expression is turned on to rapidly reach a plateau with all nuclei expressing the reporter. Consistent with a Bicoid dose-dependent activation process, the time period required to reach the plateau increases with the distance to the anterior pole. Remarkably, despite the challenge imposed by frequent mitoses and high nuclei-to-nuclei variability in transcription kinetics, it only takes 3 minutes at each interphase for the MS2 reporter loci to measure subtle differences in Bicoid concentration and establish a steadily positioned and steep (Hill coefficient ~ 7) expression boundary. Modeling based on cooperativity between the 6 known Bicoid binding sites in the hb promoter region and assuming rate limiting concentrations of the Bicoid transcription factor at the boundary is able to capture the observed dynamics of pattern establishment but not the steepness of the boundary. This suggests that additional mechanisms are involved in the steepness of the response.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Studies of morphogens: keep calm and carry on

Cited by 40 publications

References 44 publications

Collective Space-Sensing Coordinates Pattern Scaling in Engineered Bacteria

Collective Space-Sensing Coordinates Pattern Scaling in Engineered Bacteria

Visualizing retinoic acid morphogen gradients

3 minutes to precisely measure morphogen concentration

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