Tissue mechanics regulate mitotic nuclear dynamics during epithelial development

Abstract

<jats:title>Summary</jats:title><jats:p>Cell divisions are essential for tissue growth. In pseudostratified epithelia, where nuclei are staggered across the tissue, each nucleus migrates apically before undergoing mitosis. Successful apical nuclear migration is critical to preserve tissue integrity during cell division. Most previous investigations have focused on the local cellular mechanisms controlling nuclear migration. Yet, inter-species and inter-organ comparisons of different pseudostratified epithelia suggest global tissue architecture may influence nuclear dynamics, but the underlying mechanisms remain elusive. Here, we use the developing <jats:italic>Drosophila</jats:italic> wing disc to systematically investigate, in a single epithelial type, how changes in tissue architecture during growth influence mitotic nuclear migration. We observe distinct nuclear dynamics at discrete developmental stages, as epithelial morphology changes. We then use genetic and physical perturbations to show a direct effect of cell density on mitotic nuclear positioning. We also find Rho kinase and Diaphanous, which facilitate mitotic cell rounding in confined cell conditions, are essential for efficient apical nuclear movement. Strikingly, perturbation of Diaphanous causes increasing defects in apical nuclear migration as the tissue grows, and these defects can be reversed by acute physical reduction of cell density. Our findings reveal how the mechanical environment imposed on cells within a tissue alters the molecular and cellular mechanisms adopted by single cells for mitosis. We speculate that mechanical regulation of apical mitotic positioning could be a global mechanism for tissue growth control.</jats:p>

Nuclear crowding and nonlinear diffusion during interkinetic nuclear migration in the zebrafish retina

“…Finally, in G2 a concentration of myosin at the basal side of the nucleus leads to its rapid apical migration ( Leung et al, 2011 ). However, a much closer examination of molecular mechanisms driving stochastic nuclear movements is required to better understand the connections between these phenomena, as we are far from understanding the nature of all the different forces involved in this process ( Kirkland et al, 2020 ). Furthermore, the diffusion constant reported here reflects all types of nuclear movement during IKNM as it is derived from the changing nuclear concentration profile over time.…”

The Mechanics of Mitotic Cell Rounding

“…of the fly wing disc, this process depends on accumulation of actin and activated moesin at the cell cortex (Nakajima et al, 2013) as well as local tissue tension (Kirkland et al, 2019). However, in this system, unlike in cuboidal epithelia, adherens junctions are disassembled during mitosis (Aguilar-Aragon et al, 2020).…”

“…Tall, thin cells in pseudo-stratified epithelia undergo a process known as interkinetic nuclear migration prior to mitosis where the nucleus and cell body migrate to the apical surface ( Meyer et al, 2011 ; Norden, 2017 ) while maintaining attachment to the basal lamina via a thin basal process ( Kosodo et al, 2008 ). In the pseudostratified epithelium of the fly wing disc, this process depends on accumulation of actin and activated moesin at the cell cortex ( Nakajima et al, 2013 ) as well as local tissue tension ( Kirkland et al, 2019 ). However, in this system, unlike in cuboidal epithelia, adherens junctions are disassembled during mitosis ( Aguilar-Aragon et al, 2020 ).…”

Actin on and around the Nucleus

“…Coordinated actin polymerization creates a pushing force to move the nucleus toward the apical surface of pseudostratified epithelial in both of these mechanisms. Similarly, Diaphanous, the sole Dia-class formin in Drosophila, and Rok, the activator of myosin II, move the nucleus to the apical face of the developing wing disc before mitosis [10]. Strikingly, dependence on this formin grows with increasing tissue density, indicating a mechanism that is turned on in a crowded environment, when mechanical constraints on the nucleus increase.…”