Spatiotemporal control of ERK pulse frequency coordinates fate decisions during mammary acinar morphogenesis

Ender, Pascal; Gagliardi, Paolo Armando; Dobrzyński, Maciej; Frismantiene, Agne; Dessauges, Coralie; Höhener, Thomas Christoph; Jacques, Marc‐Antoine; Cohen, Andrew R.; Pertz, Olivier

doi:10.1016/j.devcel.2022.08.008

Cited by 35 publications

(38 citation statements)

References 69 publications

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“…In this way, long-range signalling through tissues is propagated as waves of cell activation that travel outwardly from signalling centres ( Deneke and Di Talia, 2018 ). Prominent examples of biological activation waves include ERK waves in the developing skin, breast, and colon and during wound closure ( Aoki et al, 2017 ; Ender et al, 2022 ; Pond et al, 2022 ), periodic activation waves in the brain ( Huang et al, 2010 ), chemoattractant waves in neutrophil swarms ( Afonso et al, 2012 ), morphogen waves during gastrulation ( Liu et al, 2021 ), waves of cell stress in bacterial biofilms ( Chou et al, 2022 ), and cAMP waves in Dictyostelium aggregation ( Tomchik and Devreotes, 1981 ). Waves can also be pathological, such as in cardiac fibrillation, where waves drive muscle contraction independently of the pacemaker ( Pandit and Jalife, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Controlling periodic long-range signalling to drive a morphogenetic transition

Ford

Manhart

Chubb

2023

eLife

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Cells use signal relay to transmit information across tissue scales. However, the production of information carried by signal relay remains poorly characterised. To determine how the coding features of signal relay are generated, we used the classic system for long-range signalling: the periodic cAMP waves that drive Dictyostelium collective migration. Combining imaging and optogenetic perturbation of cell signalling states, we find that migration is triggered by an increase in wave frequency generated at the signalling centre. Wave frequency is regulated by cAMP wave circulation, which organises the long-range signal. To determine the mechanisms modulating wave circulation, we combined mathematical modelling, the general theory of excitable media and mechanical perturbations to test competing models. Models in which cell density and spatial patterning modulate the wave frequency cannot explain the temporal evolution of signalling waves. Instead, our evidence leads to a model where wave circulation increases the ability for cells to relay the signal, causing further increase in the circulation rate. This positive feedback between cell state and signalling pattern regulates the long-range signal coding that drives morphogenesis.

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Section: Introductionmentioning

confidence: 99%

Controlling periodic long-range signalling to drive a morphogenetic transition

Ford

Manhart

Chubb

2023

eLife

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“…The regionalization of epithelial proliferation (Figure 5C) suggested an epithelial signaling response to fibroblast contact. Therefore, we examined the subcellular localization of yes associated protein (YAP), a mechano-sensor that in a resting cell resides in the cytoplasm but translocates to the nucleus upon mechanical stress (Panciera et al, 2017), and phosphorylated (active) ERK (P-ERK), the regulator of mammary epithelial branching (Ender et al, 2022; Huebner et al, 2016) as two candidates. We found that YAP specifically accumulated in the nuclei of epithelial cells in the neck region of epithelial branch (Figure 5G), indicating that the contact with contractile fibroblasts can be sensed by the underlying epithelial cells as a mechanical stress.…”

Section: Resultsmentioning

confidence: 99%

Fibroblast-induced mammary epithelial branching depends on fibroblast contractility

Sumbal

Fre

Koledová

2023

Preprint

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Epithelial branching morphogenesis is an essential process in living organisms, through which organ-specific epithelial shapes are created. Interactions between epithelial cells and their stromal microenvironment instruct branching morphogenesis but remain incompletely understood. Here we employed fibroblast-organoid or fibroblast-spheroid co-culture systems and time-lapse imaging to reveal that physical contact between fibroblasts and epithelial cells and fibroblast contractility are required to induce mammary epithelial branching. Pharmacological inhibition of ROCK or non-muscle myosin II, or fibroblast-specific knock-out of Myh9 abrogate fibroblast-induced epithelial branching. Furthermore, fibroblast-induced branching requires epithelial proliferation and is associated with distinctive epithelial patterning of YAP and ERK activity along organoid branches, which is dependent on fibroblast contractility. Together, we identify fibroblast contractility as a novel stromal factor driving mammary epithelial morphogenesis. Our study contributes to comprehensive understanding of overlapping but divergent employment of mechanically active fibroblasts in developmental versus tumorigenic programs.

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“…2D, Methods). These pathways are physiologically relevant in milk, as ERK cascade signaling has a key role in mammary morphogenesis 34 , and lipogenesis generates the energy dense fats synthesized by the lactating mammary gland 35 . To identify tissues for which genetic regulation of gene expression is most similar to milk, we measured the proportion of shared eQTLs between milk and each GTEx tissue.…”

Section: Genetic Influences On Gene Expression In Human Milkmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human milk variation is shaped by maternal genetics and impacts the infant gut microbiome

Johnson

Heisel

Allert

et al. 2023

Preprint

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Human milk is a complex mix of nutritional and bioactive components that provide complete nutrition for the infant. However, we lack a systematic knowledge of the factors shaping milk composition and how milk variation influences infant health. Here, we used multi-omic profiling to characterize interactions between maternal genetics, milk gene expression, milk composition, and the infant fecal microbiome in 242 exclusively breastfeeding mother-infant pairs. We identified 487 genetic loci associated with milk gene expression unique to the lactating mammary gland, including loci that impacted breast cancer risk and human milk oligosaccharide concentration. Integrative analyses uncovered connections between milk gene expression and infant gut microbiome, including an association between the expression of inflammation-related genes with IL-6 concentration in milk and the abundance ofBifidobacteriain the infant gut. Our results show how an improved understanding of the genetics and genomics of human milk connects lactation biology with maternal and infant health.

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Spatiotemporal control of ERK pulse frequency coordinates fate decisions during mammary acinar morphogenesis

Cited by 35 publications

References 69 publications

Controlling periodic long-range signalling to drive a morphogenetic transition

Controlling periodic long-range signalling to drive a morphogenetic transition

Fibroblast-induced mammary epithelial branching depends on fibroblast contractility

Human milk variation is shaped by maternal genetics and impacts the infant gut microbiome

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