WDR5 stabilizes actin architecture to promote multiciliated cell formation

Abstract

The actin cytoskeleton is critical to shape cells and pattern intracellular organelles to drive tissue morphogenesis. In multiciliated cells (MCCs), apical actin forms a lattice that drives expansion of the cell surface necessary to host hundreds of cilia. The actin lattice also uniformly distributes basal bodies across this surface. This apical actin network is dynamically remodeled, but the molecules that regulate its architecture remain poorly understood. We identify the chromatin modifier, WDR5, as a regulator of apical F-actin in multiciliated cells. Unexpectedly, WDR5 functions independently of chromatin modification in MCCs. Instead, we discover a scaffolding role for WDR5 between the basal body and F-actin. Specifically, WDR5 binds to basal bodies and migrates apically, where F-actin organizes around WDR5. Using a monomer trap for G-actin, we show that WDR5 stabilizes F-actin to maintain apical lattice architecture. In summary, we identify a novel, non-chromatin role for WDR5 in stabilizing F-actin in multiciliated cells.

Target-agnostic discovery of Rett Syndrome therapeutics by coupling computational network analysis and CRISPR-enabled in vivo disease modeling

“…We visualized the cilia-driven flow of fluorescent microspheres over the surface of the xenopus tadpole by taking times series with the Leica SP5 x MP inverted confocal. Our methods were based on previous reports 78 with some modifications. Stage 45 tadpoles were placed in a 24 well ߤ-Plate 14mm (ibidi, Gräfelfing, Germany), and underwent anesthesia by incubation with 1x tricaine before proceeding to image.…”

Mechanics of cell integration in vivo

“…During the formation of the mucociliary epithelium in the amphibian Xenopus embryo, successive waves of precursor cells move from the basal into the superficial tissue layer [10][11][12][13] . The first wave of migrating cells is composed of multiciliated cell (MCC) precursors, which integrate into the superficial epithelial layer composed of mucus-producing goblet cells 10,14,15 (Fig. 1a).…”

Centriole Number and the Accumulation of Microtubules Modulate the Timing of Apical Insertion during Radial Intercalation

“…Indeed, apical expansion of MCCs has been well characterized and is known to require RhoA and actin-based pushing forces [8,22]. MCCs are known to create an elaborate actin network via interactions between basal bodies and WDR5 that ultimately facilitates spacing, polarization, and metachronal synchrony of the motile cilia [23][24][25]. Furthermore, in any in vivo context, protrusive behavior involves dynamic and reciprocal changes in both the invading cell and the surrounding neighboring cells.…”