Biology subjects

Korovesi, A. G.

Publications and source records attributed to Korovesi, A. G..

4 recordsLinked to original sources

bioRxiv2025

Mechanical control of histone serotonylation initiates neural crest migration in vivo

Collective cell migration (CCM) is pivotal in several biological contexts, and posttranslational modifications of histones are essential to initiate this process1-3. Here, we show that a recently discovered chromatin mark, termed histone serotonylation4, is involved in the collective migration of cranial neural crest cells - an embryonic multipotent stem cell population5. Our in vivo data reveal that histone serotonylation appears in neural crest cells just before they start migrating and that its occurrence is essential to initiate their CCM. Surprisingly, we found that stiffening of the neural crest migratory substrate, the mesoderm, induces histone serotonylation by promoting nuclear translocation of transglutaminase 2 (Tgm2), the enzyme responsible for adding serotonin to histones4. Moreover, mechanical and molecular perturbations demonstrate that mechanical shuttling of Tgm2 into the nucleus, with concomitant increases in histone serotonylation, are both required and sufficient to allow CCM in vivo. Furthermore, integrated chromatin immunoprecipitation and RNA sequencing analyses uncover a transcriptional module, which is enabled by histone serotonylation in response to mesoderm stiffening. Altogether, our results provide in vivo evidence showing that tissue stiffening leads to increased levels of histone serotonylation to reinforce permissive patterns of gene expression, supporting the switch from non-migratory to migratory cell states.

developmental biology↗

bioRxiv2025

Piezo1-Yap1 signalling translates tissue mechanics into regenerative cell states.

Epimorphic regeneration encompasses several stages, such as wound healing, formation of a regenerative bud and regenerative outgrowth. The signatures that define each stage have been well studied, yet little is known about the mechanisms that coordinate cell state transitions across regenerative stages. Here, we show that stiffening of wounded epithelial tissues is essential for the formation of a prospective regenerative bud and, in turn, for the transition from wound healing to bud formation. Mechanistically, to detect prospective bud stiffening, cells use a mechanosensitive cascade involving Piezo1-dependent Yap1 activation. We also determined that this cascade is required for the acquisition of a transcriptional profile that endows bud cells with regenerative competence. Notably, the activation of this Piezo1-Yap1 mechanosensitive cascade in nonregenerative contexts is sufficient to induce the formation of competent bud-like structures, which are sufficient to drive de novo regeneration in these otherwise incompetent tissues. Taken together, our results reveal a mechanical state at the boundary between wound healing and regenerative bud formation, which is essential for synchronizing the transition between these pivotal stages of regeneration. More broadly, these findings support the general idea that the physical properties of tissues integrate with molecular frameworks to actuate cell state transitions during morphogenesis.

developmental biology↗

bioRxiv2023

Tgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape

The hindlimb and external genitalia of present-day tetrapods are thought to derive from an ancestral common primordium that evolved to generate a wide diversity of structures adapted for efficient locomotion and mating in the ecological niche conquered by the species. We show that despite long evolutionary distance from the ancestral condition, the early primordium of the mouse external genitalia preserved the capacity to take hindlimb fates. In the absence of Tgfbr1, the pericloacal mesoderm generates an extra pair of hindlimbs at the expense of the external genitalia. It has been shown that the hindlimb and the genital primordia share many of their key regulatory factors. Tgfbr1 controls the response to those factors by modulating the accessibility status of regulatory elements that control the gene regulatory networks leading to the formation of genital or hindlimb structures. Our work uncovers a remarkable tissue plasticity with potential implications in the evolution of the hindlimb/genital area of tetrapods, and identifies a novel mechanism for Tgfbr1 activity that might also contribute to the control of other physiological or pathological processes.

developmental biology↗

bioRxiv2022

Return of the Tbx5; lineage-tracing reveals ventricular cardiomyocyte-like precursors in the injured adult mammalian heart

The single curative measure for heart failure patients is total heart transplantation, which is limited due to a shortage of donors, the need for immunosuppression and economic costs. Therefore, there is an urgent unmet need for identifying cell populations capable of cardiac regeneration that we will be able to trace and monitor. Injury to the adult mammalian cardiac muscle, often leads to a heart attack through the irreversible loss of a large number of cardiomyocytes, due to an idle regenerative capability. Recent reports in zebrafish indicate that Tbx5a is a vital transcription factor for cardiomyocyte regeneration. Preclinical data underscore the cardioprotective role of Tbx5 upon heart failure. Data from our earlier murine developmental studies have pinpointed a prominent unipotent Tbx5-expressing embryonic cardiac precursor cell population able to form cardiomyocytes, in vivo, in vitro and ex vivo. Using a developmental approach to an adult heart injury model and by employing a lineage-tracing mouse model as well as the use of single-cell RNA-seq technology, we identify a Tbx5-expressing ventricular cardiomyocyte-like precursor population, in the injured adult mammalian heart. The transcriptional profile of that precursor cell population is closer to that of neonatal than embryonic cardiomyocyte precursors. Tbx5, a cardinal cardiac development transcription factor, lies in the centre of a ventricular adult precursor cell population, which seems to be affected by neurohormonal spatiotemporal cues. The identification of a Tbx5-specific cardiomyocyte precursor-like cell population, which is capable of dedifferentiating and potentially deploying a cardiomyocyte regenerative program, provides a clear target cell population for translationally-relevant heart interventional studies.

cell biology↗