Metabolic activities are selective modulators for individual segmentation clock processes

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

Published: Jan. 20, 2025

Abstract Numerous cellular and molecular processes during embryonic development prompt the fundamental question of how their tempos are coordinated whether a common global modulator exists. While segmentation clock tempo scales with kinetics gene expression degradation core Hes7 across mammals, coordination these remains unclear. This study examines metabolic activities serve as for clock, finding them to be selective instead. Several inhibitions extend period but affect key differently: glycolysis inhibition slows protein production delay without altering intron delay, while electron transport chain extends influencing other processes. Combinations distinct exhibit synergistic effects. We propose that scaled species may result from combined modulators shaped by evolutionary constraints, rather than single modulator.

Language: Английский

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Multiscale spatio-temporal dynamics of UBE3A gene in brain physiology and neurodevelopmental disorders

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: unknown, P. 106669 - 106669

Published: Sept. 1, 2024

The UBE3A gene, located in the chromosomal region 15q11-13, is subject to neuron-specific genomic imprinting and it plays a critical role brain development. Genetic defects of cause severe neurodevelopmental disorders, namely Angelman syndrome (AS) 15q11.2-q13.3 duplication (Dup15q). In last two decades, development vitro vivo models AS Dup15q were fundamental improve understanding function brain. However, pathogenic mechanisms these diseases remain elusive effective treatments are lacking. Recent evidence suggests that functions both spatially temporally specific, varying across subcellular compartments, regions, neuronal circuits. present review, we summarize current knowledge on pathophysiology under this spatio-temporal perspective. Additionally, propose key research questions will be instrumental better understand underpinning disorders provide rationale develop novel therapies.

Language: Английский

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Protein degradation shapes developmental tempo in mouse and human neural progenitors

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

Published: Aug. 1, 2024

ABSTRACT The speed of embryonic development varies considerably between mammalian species, yet the underlying molecular mechanisms remain poorly understood. To investigate basis for species-specific developmental tempo, we performed a comprehensive comparative analysis protein dynamics in mouse and human neural progenitors (NPs). Through combination targeted labelling, quantitative mass spectrometry, depletion with self-labeling tags, demonstrate that degradation is key driver tempo differences NPs. We observe systematic 1.5-fold increase half-lives NPs compared to mouse, independent cellular compartment or function. This difference persists post-mitotic neurons, indicating active as primary mechanism. Proteasomal activity also ∼1.5-fold higher NPs, consistent upregulation proteasome-associated proteins. Importantly, increasing rate proteolytic transcriptional repressor accelerates expression its target gene. Despite rates, synthesis rates are similar resulting content Our findings highlight central role controlling provide insight into evolutionary changes timing across species.

Language: Английский

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Single-cell multiome uncovers differences in glycogen metabolism underlying species-specific speed of development

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

Published: Sept. 3, 2024

Abstract Embryos from different mammalian species develop at characteristic timescales. These timescales are recapitulated during the differentiation of pluripotent stem cells in vitro . Specific genes and molecular pathways that modulate cell speed between remain to be determined. Here we use single-cell multi-omic analysis neural mouse, cynomolgus human identify regulators for speed. We demonstrate species-specific transcriptome dynamics mirrored chromatin level, but is insensitive manipulations growth cycling. Exploiting resolution our data, glycogen storage levels regulated by UDP-glucose pyrophosphorylase 2 (UGP2) as a species-dependent trait cells, show lowered UGP2 mutant associated with accelerated differentiation. The control energy could general strategy regulation

Language: Английский

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