The microtubule end-binding proteins EB1 and Patronin modulate the spatiotemporal dynamics of myosin and pattern pulsed apical constriction.

Apical constriction powers amnioserosa contraction during Drosophila dorsal closure. The nucleation, movement and dispersal of apicomedial actomyosin complexes generates pulsed apical constrictions during early closure. Persistent apicomedial and circumapical actomyosin complexes drive unpulsed constrictions that follow. Here, we show that the microtubule end-binding proteins EB1 and Patronin pattern constriction dynamics and contraction kinetics by coordinating the balance of actomyosin forces in the apical plane. We find that microtubule growth from moving Patronin platforms governs the spatiotemporal dynamics of apicomedial myosin through the regulation of RhoGTPase signaling by transient EB1-RhoGEF2 interactions. We uncover the dynamic reorganization of a subset of short non-centrosomally nucleated apical microtubules that surround the coalescing apicomedial myosin complex, trail behind it as it moves and disperse as the complex dissolves. We demonstrate that apical microtubule reorganization is sensitive to Patronin levels. Microtubule depolymerization compromised apical myosin enrichment and altered constriction dynamics. Together, our findings uncover the importance of reorganization of an intact apical microtubule meshwork, by moving Patronin platforms and growing microtubule ends, in enabling the spatiotemporal modulation of actomyosin contractility and, through it, apical constriction.

The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19.

Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood-brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.

Local, cell-nonautonomous feedback regulation of myosin dynamics patterns transitions in cell behavior: a role for tension and geometry?

How robust patterns of tissue dynamics emerge from heterogeneities, stochasticities, and asynchronies in cell behavior is an outstanding question in morphogenesis. A clear understanding of this requires examining the influence of the behavior of single cells on tissue patterning. Here we develop single-cell manipulation strategies to uncover the origin of patterned cell behavior in the amnioserosa during Drosophila dorsal closure. We show that the formation and dissolution of contractile, medial actomyosin networks previously shown to underlie pulsed apical constrictions in the amnioserosa are apparently asynchronous in adjacent cells. We demonstrate for the first time that mechanical stresses and Rho1 GTPase control myosin dynamics qualitatively and quantitatively, in amplitude and direction, both cell autonomously and nonautonomously. We then demonstrate that interfering with myosin-dependent contractility in single cells also influences pulsed constrictions cell nonautonomously. Our results suggest that signals and stresses can feedback regulate the amplitude and spatial propagation of pulsed constrictions through their influence on tension and geometry. We establish the relevance of these findings to native closure by showing that cell delamination represents a locally patterned and collective transition from pulsed to unpulsed constriction that also relies on the nonautonomous feedback control of myosin dynamics.