The Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration DOI Open Access

Xiao-Jun Li,

C. Lloyd Morgan, Lin Li

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

ABSTRACT Hair cells (HCs) within the inner ear cochlea are specialized mechanoreceptors required for hearing. Cochlear HCs not regenerated in mammals, and their loss is a leading cause of deafness humans. supporting (SCs) newborn mice have capacity to regenerate HCs, but persistent Notch signaling, presumably activated by SC-specific ligand Jagged1 (JAG1), prevents SCs from converting into HCs. Here, employing an organoid platform, we show that while JAG1 participates HC-fate repression, JAG1’s primary function preserve “progenitor-like characteristics” cochlear SCs. Transcriptomic mechanistic studies reveal JAG1/Notch signaling maintains expression progenitor metabolic genes sustains pro-growth pathways, including PI3K-Akt-mTOR mediated Notch1 Notch2. Finally, stimulation with JAG1-Fc peptide enhances HC-forming undergoing maturation explants vivo .

Language: Английский

Aerobic glycolysis and lactate regulate histone H3K18Lactylation occupancy to fine-tune gene expression in developing and mature retina DOI Creative Commons
Mohita Gaur,

Xulong Liang,

Matthew J. Brooks

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 20, 2025

Summary High aerobic glycolysis in retinal photoreceptors, as cancer cells, is implicated mitigating energy and metabolic demands. Lactate, a product of glycolysis, plays key role epigenetic regulation through histone lactylation cancer. Here, we demonstrate that increased ATP production during development achieved primarily augmented glycolysis. Histone lactylation, especially H3K18La, parallels enhanced lactate developing retina explants. Multi-omics analyses, combined with confocal imaging, reveal the localization H3K18La near H3K27Ac euchromatin at promoters active genes. gene expression are also concordant glucose metabolism Evaluation accessible chromatin marked uncovers an enrichment GC-rich motifs for transcription factors SP, KMT KLF families, among others, indicating specificity H3K18La-mediated regulation. Our results highlight glycolysis/lactate/H3K18La regulatory axis fine-tuning mature retina.

Language: Английский

Citations

0
The Notch ligand Jagged1 plays a dual role in cochlear hair cell regeneration DOI Open Access

Xiao-Jun Li,

C. Lloyd Morgan, Lin Li

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

ABSTRACT Hair cells (HCs) within the inner ear cochlea are specialized mechanoreceptors required for hearing. Cochlear HCs not regenerated in mammals, and their loss is a leading cause of deafness humans. supporting (SCs) newborn mice have capacity to regenerate HCs, but persistent Notch signaling, presumably activated by SC-specific ligand Jagged1 (JAG1), prevents SCs from converting into HCs. Here, employing an organoid platform, we show that while JAG1 participates HC-fate repression, JAG1’s primary function preserve “progenitor-like characteristics” cochlear SCs. Transcriptomic mechanistic studies reveal JAG1/Notch signaling maintains expression progenitor metabolic genes sustains pro-growth pathways, including PI3K-Akt-mTOR mediated Notch1 Notch2. Finally, stimulation with JAG1-Fc peptide enhances HC-forming undergoing maturation explants vivo .

Language: Английский

Citations

0