Biology subjects

Suli, A.

Publications and source records attributed to Suli, A..

5 recordsLinked to original sources

bioRxiv2025

Microtubule architecture connects AMOT stability to YAP/TAZmechanotransduction and Hippo signaling

Cellular mechanotransduction is a fundamental informational system by which cells read the structural features of their environment to control their own form and function. The YAP/TAZ transcriptional regulators are universal effectors of physical signals. Yet, the identity of proteins and subcellular structures serving as mechano-rheostats remains elusive. Here we demonstrate that perinuclear centrosome and microtubules architecture act functionally downstream of F-actin as cornerstones of cellular mechanotransduction. The mechanism revolves around the stability of AMOT proteins, that act as cytoplasmic inhibitory sinks for YAP/TAZ. Being degraded in mechano-activated cells and stabilized in mechanically-inhibited cells, AMOT serves as primary mechanical rheostat. In mechanically inhibited cells, microtubules form a cage-like network surrounding the nucleus, but, in mechanically activated cells, switch their architecture with formation of the centrosome from which microtubules sprout toward the cell periphery. In these conditions, AMOT proteins bound to the Dynein/Dynactin complex are subject to fast retrograde transport through the microtubular aster toward the pericentrosomal proteasome for quantitative and timely degradation. Restoring centrosomal condensation in mechanically inhibited cells by NLP1 overexpression is sufficient to restore mechanosignaling and YAP activation. AMOT proteins serves as universal integrator of distinct physical inputs from the ECM and the cytoskeleton, and their ablation renders cells invariably mechano-insensitive. Our findings also provide a unifying model that mechanistically merges mechanosignaling with the Hippo cascade. The current model by which YAP/TAZ are regulated by Hippo kinases is through direct YAP/TAZ phosphorylation. Our data instead show that, at least in the context of mechanotransduction, Hippo signaling inhibits YAP/TAZ largely indirectly, through LATS phosphorylation of AMOT averting it from its degradation route. We further show that Ras/RTK oncogenes hijack the AMOT degradation route to promote YAP/TAZ-mediated tumorigenesis. The findings imply the AMOT stabilization machinery as novel target for YAP/TAZ therapeutic modulation. In sum, our work reveals a previously unknown hierarchical coordination of distinct cytoskeletal and transport systems orchestrating mechanosignaling at the whole cell level.

cell biology↗

bioRxiv2025

Pharmacological inhibition of all known major inward cationic currents does not block the induction of spreading depolarizations

Spreading depolarization (SD) is a wave of profound cellular depolarization that propagates across central nervous system tissue and causes a near-complete collapse of ionic gradients. Implicated in neuropathologies including seizures, migraine with aura, traumatic brain injury, and stroke, SD is experimentally induced in animals by electrical stimulation, mechanical injury, hypoxia, elevated extracellular potassium, and various other techniques. Despite extensive research, the mechanisms underlying SD initiation remain unclear. Prior research in rodents found that simultaneously blocking sodium, calcium, and glutamatergic (AMPA and NMDA) channels prevents SD induction whereas inhibiting any two of these three currents is insufficient. This suggests that SD induction could be a product of overstimulation of any single known inward cationic current. However, some researchers propose that SD induction occurs via an unknown "SD channel." To further explore the role of known inward cationic currents in SD induction, we applied high potassium to two biological models, namely zebrafish and mice. First, we developed a novel ex vivo zebrafish model to assess SD induction in the optic tectum. Using KCl microinjection and DC local field potential recordings, we found that inhibition of sodium, calcium, and glutamatergic channels significantly decreased SD amplitude but never blocked SD induction in the zebrafish optic tectum. Similar pharmacological experiments in hippocampal mouse slices (CA1 subregion) also confirmed that SDs persist despite the same pharmacological cocktail. These findings suggest that additional mechanisms beyond sodium, calcium, and glutamatergic signaling contribute to SD induction, supporting the hypothesis that a currently unknown channel is critical in SD physiology.

neuroscience↗

bioRxiv2025

YAP/TAZ mechanotransduction is a fast cellular response to subnuclear adhesions revealed by mechanically dynamic substrates

Mechanotransduction, the conversion of mechanical cues into biochemical signals, is a cardinal regulator of myriad cell behaviors. However, the precise timing by which mechanical signals are sensed and relayed to the nucleus remains poorly understood. To address this gap, we developed dynamically degradable polyacrylamide (DPAA) hydrogels that allow in situ modulation of substrate stiffness while maintaining continuous cell adhesion, thereby mimicking physiological mechanical transitions. Using these tools, we discovered that YAP/TAZ, key mechanosensitive transcription factors, respond rapidly to changes in substrate stiffness primarily through changes in subnuclear adhesions. As substrate softening reaches the low kPa threshold (<2kPa), subnuclear adhesions and their associated ventral actin fibers disassemble within minutes, concurrently causing cytoplasmic relocalization of YAP/TAZ. In cells experiencing such a continuum of mechanical states, peripheral focal adhesions remained surprisingly stable while undergoing continuous remodeling, suggesting a more resilient and adaptable mechanism of force transmission than previously modeled. Our time-resolved results indicate that subnuclear adhesions act as rapid mechanotransduction nodes, leading to YAP/TAZ-mediated nuclear responses independently of peripheral adhesion dynamics. This enhanced understanding of YAP/TAZ regulation should advance the field of mechanobiology and offers potential insights for manipulating cellular responses in regenerative medicine and cancer therapy.

bioengineering↗

bioRxiv2022

VALPROIC ACID AFFECTS NEURONAL SPECIFICATION AND DIFFERENTIATION DURING EARLY OPTIC TECTUM DEVELOPMENT OF ZEBRAFISH

The mammalian superior colliculus and its non-mammalian homolog, the optic tectum (OT), are midbrain structures that integrate multimodal sensory inputs and guide non-voluntary movements in response to prevalent stimuli. Recent studies have implicated this structure as a possible site affected in Autism Spectrum Disorder (ASD). Interestingly, fetal exposure to valproic acid (VPA) has also been associated with an increased risk of ASD in humans and animal models. Therefore, we took the approach of determining the effects of VPA treatment on zebrafish OT development as a first step in identifying the mechanisms that allow its formation. We describe the normal OT development during the first 5 days of development and show that in VPA treated embryos, while proliferation of the OT neuroepithelium continued, neuronal specification stalled. This was followed by impairment of neurite extension and complexity, suggesting that in addition to neurogenesis, VPA treatment affects axonogenesis and dendritogenesis. VPA treatment was most detrimental during the first three days of development and did not appear to be linked to oxidative stress. In conclusion, our work provides a foundation for research into mechanisms driving OT development, as well as the relationship between the OT, VPA, and ASD.

developmental biology↗

bioRxiv2021

Single-Cell RNA Sequencing Characterizes the Molecular Heterogeneity of the Larval Zebrafish Optic Tectum

The optic tectum (OT) is a multilaminated midbrain structure that acts as the primary retinorecipient in the zebrafish brain. Homologous to the mammalian superior colliculus, the OT is responsible for the reception and integration of stimuli, followed by elicitation of salient behavioral responses. While the OT has been the focus of functional experiments for decades, less is known concerning specific cell types, microcircuitry, and their individual functions within the OT. Recent efforts have contributed substantially to the knowledge of tectal cell types; however, a comprehensive cell catalog is incomplete. Here we contribute to this growing effort by applying single-cell RNA-sequencing (scRNA-seq) to characterize the transcriptomic profiles of tectal cells labeled by the transgenic enhancer trap line y304Et(cfos:Gal4;UAS:Kaede). We sequenced 13,320 cells, a 4X cellular coverage, and identified 25 putative OT cell populations. Within those cells, we identified several mature and developing neuronal populations, as well as non-neuronal cell types including oligodendrocytes, microglia, and radial glia. Although most mature neurons demonstrate GABAergic activity, several glutamatergic populations are present, as well as one glycinergic population. We also conducted Gene Ontology analysis to identify enriched biological processes, and computed RNA velocity to infer current and future transcriptional cell states. Finally, we conducted in situ hybridization to validate our bioinformatic analyses and spatially map select clusters. In conclusion, the larval zebrafish OT is a complex structure containing at least 25 transcriptionally distinct cell populations. To our knowledge, this is the first time scRNA-seq has been applied to explore the OT alone and in depth.

neuroscience↗