Mannose controls mesoderm specification and symmetry breaking in mouse gastruloids

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(12), P. 1523 - 1537.e6

Published: April 17, 2024

Patterning and growth are fundamental features of embryonic development that must be tightly coordinated. To understand how metabolism impacts early mesoderm development, we used mouse stem-cell-derived gastruloids, co-expressed glucose transporters with the mesodermal marker T/Bra. We found mimic, 2-deoxy-D-glucose (2-DG), blocked T/Bra expression abolished axial elongation in gastruloids. However, removal did not phenocopy 2-DG treatment despite a decline glycolytic intermediates. As can also act as competitive inhibitor mannose protein glycosylation, added together it could rescue specification both vivo vitro. further showed blocking production intracellular recycling abrogated specification. Proteomics analysis demonstrated reversed glycosylation Wnt pathway regulator, secreted frizzled receptor Frzb. Our study controls

Language: Английский

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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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Historic obstacles and emerging opportunities in the field of developmental metabolism – lessons from Heidelberg

Development, Journal Year: 2024, Volume and Issue: 151(12)

Published: June 15, 2024

The field of developmental metabolism is experiencing a technological revolution that opening entirely new fields inquiry. Advances in metabolomics, small-molecule sensors, single-cell RNA sequencing and computational modeling present opportunities for exploring cell-specific tissue-specific metabolic networks, interorgan communication, gene-by-metabolite interactions time space. Together, these advances not only means by which biologists can tackle questions have challenged the centuries, but also young scientists with to define areas These emerging frontiers were at center highly interactive 2023 EMBO workshop 'Developmental metabolism: flows energy, matter, information'. Here, we summarize key discussions from this forum, emphasizing modern biology's challenges opportunities.

Language: Английский

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Mannose is crucial for mesoderm specification and symmetry breaking in gastruloids

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 7, 2023

Abstract Patterning and growth are fundamental features of embryonic development that must be tightly coordinated during morphogenesis. As metabolism can control cell while also providing mechanistic links to developmental signalling pathways, it is ideally placed enable this coordination. To understand how impacts early mesoderm specification, we used mouse stem (ES) cell-derived gastruloids, as these temporal over metabolic manipulations generated in large quantities. Gastruloids show mosaic expression two glucose transporters, Slc2a1 Slc2a3 both which co-express with the mesodermal marker T/Bra neural Sox2 . significance cellular uptake development, inhibitor 2-deoxy-D-glucose (2-DG). 2-DG specifically blocks without affecting abolishes axial elongation gastruloids. Surprisingly, removing completely from medium did not phenocopy treatment despite a significant decline glycolytic intermediates occurring under conditions. act competitive mannose, added mannose together found could rescue specification. Together, our results crucial for pathway dispensable at stages

Language: Английский

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Integrated Molecular-Phenotypic Profiling Reveals Metabolic Control of Morphological Variation in Stembryos

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 5, 2023

SUMMARY Mammalian stem-cell-based models of embryo development (stembryos) hold great promise in basic and applied research. However, considerable phenotypic variation despite identical culture conditions limits their potential. The biological processes underlying this seemingly stochastic are poorly understood. Here, we investigate the roots by intersecting transcriptomic states morphological history individual stembryos across stages modeling post-implantation early organogenesis. Through machine learning integration time-resolved single-cell RNA-sequencing with imaging-based quantitative profiling, identify features predictive end-state. Leveraging power revealed that imbalance oxidative phosphorylation glycolysis results aberrant morphology a neural lineage bias can be corrected metabolic interventions. Collectively, our work establishes divergent as drivers variation, offers broadly applicable framework to chart predict organoid systems. strategy leveraged control processes, ultimately increasing reproducibility vitro Highlights Time-resolved charting hundreds generates molecular fingerprints Machine identifies end-state Early cellular composition Metabolic interventions tune stembryo correct derailment differentiation outcomes

Language: Английский

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Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 18, 2023

Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health longevity. Nevertheless, functional-metabolic within heterogenous microenvironments in vivo remains poorly understood due to complexity metabolic plasticity. Here, we establish the Drosophila renal system paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, organ-wide physiology. Kidneys are amongst most energetically-demanding organs, yet exactly how individual cell types fine-tune meet their diverse, unique physiologies over life-course unclear. Integrating live-imaging metabolite organelle dynamics with spatio-temporal genetic perturbation intact functional tissue, uncover distinct signatures essential support healthy ageing. Cell type-specific programming glucose handling, PPP-mediated glutathione regeneration FA β-oxidation via dynamic lipid-peroxisomal networks, downstream differential ERR receptor activity, precisely match energetic demands whilst limiting damage premature senescence; however, dramatic dysregulation may underlie age-related dysfunction.

Language: Английский

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Perspectives in collective cell migration – moving forward

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(12)

Published: June 15, 2024

Collective cell migration, where cells move as a cohesive unit, is vital process underlying morphogenesis and cancer metastasis. Thanks to recent advances in imaging modelling, we are beginning understand the intricate relationship between its microenvironment how this shapes polarity, metabolism modes of migration. The use biophysical mathematical models offers fresh perspective on migrate collectively, either flowing fluid-like state or transitioning more static states. Continuing unite researchers biology, physics mathematics will enable us decode complex biological behaviours that underly collective migration; only then can coordinated movement influences formation organisation tissues directs spread metastatic cancer. In Perspective, highlight exciting discoveries, emerging themes common challenges have arisen years, possible ways forward bridge gaps our current understanding

Language: Английский

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The proteomic landscape and temporal dynamics of mammalian gastruloid development

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 7, 2024

Gastrulation is the highly coordinated process by which early embryo breaks symmetry, establishes germ layers and a body plan, sets stage for organogenesis. As mammalian development challenging to study

Language: Английский

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Gastruloids — a minimalistic model to study complex developmental metabolism

Emerging Topics in Life Sciences, Journal Year: 2023, Volume and Issue: 7(4), P. 455 - 464

Published: Dec. 18, 2023

Metabolic networks are well placed to orchestrate the coordination of multiple cellular processes associated with embryonic development such as cell growth, proliferation, differentiation and movement. Here, we discuss advantages that gastruloids, aggregates mammalian stem cells self-assemble a rudimentary body plan, have for uncovering instructive role metabolic pathways play in directing developmental processes. We emphasise importance using reductionist systems link specific defined events early their utility obtaining enough material metabolomic studies. Finally, review ways which basic gastruloid protocol can be adapted obtain models types, tissues regions. Together, propose gastruloids an ideal system rapidly uncover new mechanistic links between signalling networks, then inform precise vivo studies confirm function embryo.

Language: Английский

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Transitions in development – an interview with Berna Sozen

Development, Journal Year: 2024, Volume and Issue: 151(2)

Published: Jan. 15, 2024

Berna Sozen is an Assistant Professor in the Department of Genetics at Yale University, USA. Berna's lab studies early mammalian development, metabolism, and maternal–fetal interactions using mouse human embryos, as well stem cell-derived embryo-like models. In 2022, received NIH Director's New Innovator Award. We spoke to over Zoom learn more about her journey becoming a group leader importance making science careers accessible.

Language: Английский

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