Cell shape noise strength regulates shape dynamics during EMT-associated cell spreading DOI Creative Commons
Wolfram Pönisch, Iskra Yanakieva, Guillaume Salbreux

et al.

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

Published: Oct. 15, 2024

ABSTRACT Cellular shape is intimately linked to cell function and state, transitions between states are tightly coupled changes. Yet, has been largely overlooked in state studies. Here, we combine morphometric analysis with theoretical modeling molecular perturbations interrogate dynamics during epithelial-to-mesenchymal transition (EMT). Using stochastic inference, extract the morphogenetic landscape underlying EMT. We show that within this landscape, EMT-associated spreading reflects a attractors. Strikingly, observe peak noise strength concomitant spreading, higher accelerates Our framework will be widely applicable quantitative investigations physiology disease. Together, our results identify key role for cellular stochasticity as regulator of change rates, highlight yield rich phenotypic information enhance understanding states.

Language: Английский

Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action DOI Creative Commons
Patricia Wu, Francisco Barros-Becker, Roberto Ogelman

et al.

Frontiers in Neurology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 14, 2024

Mechanosensory hair cells of the inner ears and lateral line vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing balance disorders. An important example is cell loss due exposure toxic agents including therapeutic drugs such as aminoglycoside antibiotics neomycin gentamicin antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced death zebrafish cells. Neomycin results from acute most dying within 1 h exposure. By contrast, primarily delayed death, taking up 24 maximal effect. Washout experiments demonstrate that does not require continuous exposure, demonstrating mechanisms where downstream responses differ their timing. Acute associated mitochondrial calcium fluxes can be alleviated by mitochondrially-targeted antioxidant mitoTEMPO, while independent these factors. Conversely lysosomal accumulation reduced altering endolysosomal function, sensitive manipulations. These reveal complexity closely related compounds, suggesting intervention focusing on early events rather than specific may a successful strategy.

Language: Английский

Citations

2
Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action DOI Creative Commons
Patricia Wu, Francisco Barros-Becker, Roberto Ogelman

et al.

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

Published: May 31, 2024

Mechanosensory hair cells of the inner ears and lateral line vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing balance disorders. An important example is cell loss due exposure toxic agents including therapeutic drugs such as aminoglycoside antibiotics neomycin gentamicin antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced death zebrafish cells. Neomycin results from acute most dying within 1 hour exposure. By contrast, primarily delayed death, taking up 24 hours maximal effect. Washout experiments demonstrate that does not require continuous exposure, demonstrating mechanisms where downstream responses differ their timing. Acute associated mitochondrial calcium fluxes can be alleviated by mitochondrially-targeted antioxidant mitoTEMPO, while independent these factors. Conversely lysosomal accumulation reduced altering endolysosomal function, sensitive manipulations. These reveal complexity closely related compounds, suggesting intervention focusing on early events rather than specific may a successful strategy.

Language: Английский

Citations

0
In preprints: theme and variations on hair-cell regeneration in zebrafish DOI Creative Commons
Jerónimo R. Miranda-Rodríguez, Hernán López‐Schier

Development, Journal Year: 2024, Volume and Issue: 151(14)

Published: July 15, 2024

Imagine reaching old age and still being able to engage effortlessly in conversations (Cheslock De Jesus, 2023). This possibility hinges on preserving the mechanosensory hair cells we are born with, which mammals exceptionally long-lived but, with very few exceptions, cannot be replaced once lost (Kirkegaard Jørgensen, 2000; Savas, In humans, loss of these results chronic hearing deficits, making everyday activities such as conversing noisy settings or talking phone overwhelming challenges (Reynard Thai-Van, 2024). For many, this impairment not only isolates them from social interactions but also aggravates mental health issues anxiety depression (Luppa et al., Most insights into maintaining function come studying non-mammalian vertebrates, can regenerate naturally throughout their lives (Choi 2024; Denans 2019; Pinto-Teixeira 2013; Benkafadar Emerging research is revealing that multiple mechanisms regulate hair-cell regeneration, even within same species, offering hope for future breakthroughs treating humans.Among most studied hair-cell-bearing organs neuromasts lateral line, enable fishes amphibians detect low-frequency mechanical fluctuations surrounding water (Valera 2021; Tidswell These aquatic vertebrates use line orient relative flow direction, escape predators locate prey, develop avoidance reactions. The take a more prominent role when vision limited (Montgomery 2000). Fishes have ears, constituent control balance high-frequency signals (Liu Bagnall, Importantly, ears must remain functional life animal, despite persistent environmental insult cells. zebrafish has always offered researchers two key advantages (Barrallo-Gimeno Llorens, 2022; Plazas Elgoyhen, Holmgren Sheets, Pickett Raible, 2019). First, unparalleled accessibility high-resolution microscopy, chiefly thanks its superficial location availability many lines expressing various genetically encoded fluorescent makers label different cell types (Pinto-Teixeira 2015; Hewitt Second, quickly easily eliminated using pharmacological, genetic physical approaches. ensuing recovery occurs days, enabling high temporal-resolution recording entire regenerative process 2013). recent years, advances single-cell transcriptomics added above (Lush Baek Kozak 2020). Single-cell RNA sequencing (scRNA-seq) hairpin chain reaction-based situ hybridization (HCR-FISH) helped molecularly characterize cellular sub-populations (Shi Moreover, easy production mutant animals gives access molecular components drive regeneration (Parvez 2024).The initial discovery resident progenitors took place almost decades ago (López-Schier Hudspeth, 2006). Every study followed agreed general mechanism follows series steps start birth new pairs mitotic division unipotent (UHCP; Thomas Mackenzie 2012). Although it been established how supporting re-enter mitosis after death, direct UHCP behavior remained obscure (Kozak preprint, Bell colleagues evidence scRNA-seq experiments showing gene foxg1a expressed during (Bell 2024 preprint). They allele find reduced number neuromast formation. Using nls-Eos transgenic photoconvertible protein disentangle effect fox1ga mutants neuromast, they conclude Foxg1a controls proliferation population isl1a-expressing central progenitor cells.However, nagging issue field found ear zebrafish, readily (Jimenez 2022). There currently no known marker specific UHCP, unambiguous identification achieved live videomicroscopy Therefore, one explanation finding much difficult image live. Another described simply do exist ear. another Beaulieu show robust through markedly differs neuromasts, resembling closely birds (Beaulieu preprint; Bhave 1995). Here, ablation, arise transdifferentiation pool Transdifferentiation identity conversion without an immediate intervening (Wang traditionally term reserved interconversion between belonging lineages, agree authors preprint sensu lato would entail any postmitotic another. transient wave precursor otherwise depleted by continuous maintain stable preprint) used data HCR-FISH distinguish location: cabp1b-positive recently differentiated peripheral, whereas scn5lab-expressing located centrally ear's crista. A clever combination capsaicin-mediated ablation system allowed measure possible alternative interpretation inner produces pairs, does, progenitor. Then, identically birds, immediately takes mature identity, sibling remains hidden dormant immature state until further death induces emergence (Stone Rubel, Regardless, interesting what mammalian and, therefore, may clinically relevant humans.Together, preprints highlight need combine studies understand regeneration. will benefit taking advantage scRNA-seq-derived data, together newly-developed phiC31 Integrase Genomic Loci Engineered Transgenesis (pIGLET) generate diverse reproducible expression patterns compare populations behave (Lalonde Brown 2023).Beaulieu al. (2024 now accepted as: Beaulieu, M. O., Thomas, E. D. W. (2024). temporally uncoupled expansion Development 151, dev202944. doi:10.1242/dev.202944.

Language: Английский

Citations

0
Long-range Atoh1 enhancers maintain competency for hair cell regeneration in the inner ear DOI Creative Commons
Tuo Shi, Yeeun Kim, Juan Llamas

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(51)

Published: Dec. 13, 2024

During tissue regeneration, lineage-related cells can switch their fate to replace missing cells. This cell plasticity is particularly prominent in more regenerative vertebrates such as zebrafish, yet the molecular basis by which transdifferentiate into another type upon injury remains unclear. Here, we investigate epigenetic of transdifferentiation inner ear, where supporting (SCs) generate mechanosensory hair (HCs) damage. By comparing chromatin landscapes zebrafish and green anole lizards versus nonregenerative mice, identified a class enhancers that function progenitors HCs then are selectively maintained SCs regenerate HCs. In particular, uncovered syntenic long-range for Atoh1 , master transcription factor HC differentiation. absence injury, these maintain accessibility through adulthood but prevented from driving atoh1a expression Notch repression. Deletion not only impaired formation during development also blocked ability regeneration. Moreover, defects were specific ear lateral line, revealing distinct mechanisms regeneration organs. These findings reveal enhancer maintains competency upregulate We propose continued developmental one may be common theme underlying adult vertebrates.

Language: Английский

Citations

0
Cell shape noise strength regulates shape dynamics during EMT-associated cell spreading DOI Creative Commons
Wolfram Pönisch, Iskra Yanakieva, Guillaume Salbreux

et al.

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

Published: Oct. 15, 2024

ABSTRACT Cellular shape is intimately linked to cell function and state, transitions between states are tightly coupled changes. Yet, has been largely overlooked in state studies. Here, we combine morphometric analysis with theoretical modeling molecular perturbations interrogate dynamics during epithelial-to-mesenchymal transition (EMT). Using stochastic inference, extract the morphogenetic landscape underlying EMT. We show that within this landscape, EMT-associated spreading reflects a attractors. Strikingly, observe peak noise strength concomitant spreading, higher accelerates Our framework will be widely applicable quantitative investigations physiology disease. Together, our results identify key role for cellular stochasticity as regulator of change rates, highlight yield rich phenotypic information enhance understanding states.

Language: Английский

Citations

0