Selective utilization of glucose metabolism guides mammalian gastrulation

Nature, Journal Year: 2024, Volume and Issue: 634(8035), P. 919 - 928

Published: Oct. 16, 2024

The prevailing dogma for morphological patterning in developing organisms argues that the combined inputs of transcription factor networks and signalling morphogens alone generate spatially temporally distinct expression patterns. However, metabolism has also emerged as a critical developmental regulator

Language: Английский

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A guide to ERK dynamics, part 2: downstream decoding

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(23), P. 1909 - 1928

Published: Dec. 1, 2023

Signaling by the extracellular signal-regulated kinase (ERK) pathway controls many cellular processes, including cell division, death, and differentiation. In this second installment of a two-part review, we address question how ERK exerts distinct context-specific effects on multiple processes. We discuss dynamics activity induce selective changes in gene expression programs, with insights from both experiments computational models. With focus single-cell biosensor-based studies, summarize four major functional modes for signaling tissues: adjusting size populations, gradient-based patterning, wave propagation morphological changes, diversification states. These operation are disrupted cancer other related diseases represent potential targets therapeutic intervention. By understanding dynamic mechanisms involved signaling, there is pharmacological strategies that not only simply inhibit ERK, but also restore patterns improve disease outcomes.

Language: Английский

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An improved Erk biosensor detects oscillatory Erk dynamics driven by mitotic erasure during early development

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(23), P. 2802 - 2818.e5

Published: Sept. 15, 2023

Extracellular signal-regulated kinase (Erk) signaling dynamics elicit distinct cellular responses in a variety of contexts. The early zebrafish embryo is an ideal model to explore the role Erk vivo, as gradient activated diphosphorylated (P-Erk) induced by fibroblast growth factor (Fgf) at blastula margin. Here, we describe improved Erk-specific biosensor, which term modified translocation reporter (modErk-KTR). We demonstrate utility this biosensor vitro and developing Drosophila embryos. Moreover, show that Fgf/Erk dynamic coupled tissue during both development. activity rapidly extinguished just prior mitosis, refer mitotic erasure, inducing periods inactivity, thus providing source heterogeneity asynchronously dividing tissue. Our transgenic lines represent important resource for interrogating vivo.

Language: Английский

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The mitogen-activated protein kinase network, wired to dynamically function at multiple scales

Current Opinion in Cell Biology, Journal Year: 2024, Volume and Issue: 88, P. 102368 - 102368

Published: May 15, 2024

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated (ERK) signaling network is a key transducer of signals from various receptors, including receptor tyrosine kinases (RTKs). It controls cell-cycle entry, survival, motility, differentiation, as well other fates. After four decades studying this pathway with biochemical methods, the use fluorescent biosensors has revealed dynamic behaviors such ERK pulsing, oscillations, and amplitude-modulated activity. Different RTKs equip MAPK specific feedback mechanisms to encode these different dynamics, which are then subsequently decoded into cytoskeletal events transcriptional programs, actuating cellular Recently, collective wave have been observed in multiple systems coordinate dynamics fate decisions within cell collectives. This emphasizes that correct understanding requires it at scales.

Language: Английский

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Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells

Development, Journal Year: 2022, Volume and Issue: 149(4)

Published: Feb. 15, 2022

Signal transduction networks generate characteristic dynamic activities to process extracellular signals and guide cell fate decisions such as divide or differentiate. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, only a few studies have addressed the activity signaling network in at high time resolution. Here, we use live sensors wild-type Fgf4-mutant mouse embryonic stem measure ERK single cells, for defined ligand concentrations states. These reveal pulses activity. Pulsing patterns are heterogeneous between individual cells. Consecutive pulse sequences occur more frequently than expected from simple stochastic models. Sequences become prevalent with higher concentration, but rarer differentiated Our results suggest that operates vicinity transition point oscillatory non-oscillatory dynamics resulting add new dimension cellular heterogeneity may be linked divergent cultures.

Language: Английский

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A guide to ERK dynamics, part 1: mechanisms and models

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(23), P. 1887 - 1907

Published: Dec. 1, 2023

Extracellular signal-regulated kinase (ERK) has long been studied as a key driver of both essential cellular processes and disease. A persistent question how this single pathway is able to direct multiple cell behaviors, including growth, proliferation, death. Modern biosensor studies have revealed that the temporal pattern ERK activity highly variable heterogeneous, critically, these dynamic differences modulate fate. This two-part review discusses current understanding in pathway, it regulates decisions, fates lead tissue regulation pathology. In part 1, we cover optogenetic live-cell imaging technologies first nature ERK, well challenges data analysis. We also discuss advances mathematical models for mechanisms dynamics, receptor-level regulation, negative feedback, cooperativity, paracrine signaling. While hurdles still remain, clear higher spatial resolution provide mechanistic insights into circuitry. Exciting new algorithms advanced computational tools enable quantitative measurements single-cell activation, which turn inform better behavior. However, fact cannot fully recapitulate diversity responses calls deeper network structure signal transduction general.

Language: Английский

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Are physiological oscillationsphysiological?

The Journal of Physiology, Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 25, 2023

Abstract Despite widespread and striking examples of physiological oscillations, their functional role is often unclear. Even glycolysis, the paradigm example oscillatory biochemistry, has seen questions about its function. Here, we take a systems approach to argue that oscillations play critical roles, such as enabling avoid desensitization, chronically high therefore toxic levels chemicals, become more resistant noise. Oscillation also enables complex reconcile incompatible conditions oxidation reduction, by cycling between them, synchronize many small units into one large effect. In pancreatic β‐cells, glycolytic with calcium mitochondrial drive pulsatile insulin release, for liver regulation glucose. addition, oscillation can keep biological time, essential embryonic development in promoting cell diversity pattern formation. The importance processes requires re‐thinking traditional doctrine homeostasis, holding quantities are maintained at constant equilibrium values, view largely failed clinic. A dynamic will initiate shift our health disease. deeper look mechanisms create, sustain abolish language nonlinear dynamics, well beyond linearization techniques control theory. Nonlinear dynamics us identify (‘pacemaking’) cellular, tissue system levels. image

Language: Английский

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Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell types in embryonic stem cells

Development, Journal Year: 2021, Volume and Issue: 148(21)

Published: Oct. 15, 2021

During embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types are specified from populations multipotent precursor cells. Molecular mechanisms that enable both robust cell-type proportioning despite variable initial conditions in the cells, re-establishment these upon perturbations a developing remain to be characterized. Here, we report differentiation epiblast-like primitive endoderm-like cells mouse stem cultures emerges at population level through cell-cell communication via short-range fibroblast growth factor 4 (FGF4) signal. We characterize molecular dynamical properties mechanism show how it controls wide range experimentally controlled conditions, as well autonomous following isolation one type. The generation maintenance discrete is new function for FGF signaling might operate tissues.

Language: Английский

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Optogenetic manipulation identifies the roles of ERK and AKT dynamics in controlling mouse embryonic stem cell exit from pluripotency

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(12), P. 1022 - 1036.e4

Published: May 18, 2023

Language: Английский

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Deciphering the history of ERK activity from fixed-cell immunofluorescence measurements

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 21, 2025

Abstract The RAS/ERK pathway plays a central role in diagnosis and therapy for many cancers. ERK activity is highly dynamic within individual cells drives cell proliferation, metabolism, other processes through effector proteins including c-Myc, c-Fos, Fra-1, Egr-1. These are sensitive to the dynamics of activity, but it not clear what extent pattern an determines protein expression, or how much information about embedded expression. Here, we evaluate these relationships using live-cell biosensor measurements multiplexed with immunofluorescence staining downstream target pathway. Combining datasets linear regression, machine learning, differential equation models, develop interpretive framework data, wherein Fra-1 pRb levels imply long-term activation signaling, while Egr-1 c-Myc indicate more recent activation. Analysis multiple cancer lines reveals distorted relationship between state malignant cells. We show that this can infer various classes from stains heterogeneous population, providing basis annotating fixed

Language: Английский

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