RYK-mediated filopodial pathfinding facilitates midgut elongation

Abstract

Between embryonic day 10.5 to 14.5, active proliferation drives rapid elongation of the murine midgut epithelial tube. Within this pseudostratified epithelium, nuclei synthesize DNA near the basal surface and move apically to divide. After mitosis, the majority of daughter cells extend a long, basally oriented filopodial protrusion, building a de novo path along which their nuclei can return to the basal side. WNT5A, secreted by surrounding mesenchymal cells, acts as a guidance cue to orchestrate this epithelial pathfinding behavior, but how this signal is received by epithelial cells is unknown. Here, we investigated two known WNT5A receptors, ROR2 and RYK. We found that epithelial ROR2 is dispensable for midgut elongation. However, loss of Ryk phenocopies the Wnt5a−/− phenotype, perturbing post-mitotic pathfinding and leading to apoptosis. These studies reveal that the ligand-receptor pair, WNT5A-RYK, acts as a navigation system to instruct filopodial pathfinding, a process critical for continuous cell cycling to fuel rapid midgut elongation.

Vanglfacilitates mesenchymal thinning during lung sacculation independently ofCelsr

“…Of these receptors, Ryk shows the strongest expression in the lung during this developmental period, with highest expression in the lung mesenchyme. Each of these receptors has been hypothesized or shown to function downstream of Wnt5a, a non-canonical Wnt ligand (Gao et al, 2011; Martinez et al, 2015; Wang et al, 2020). Consistently, the scRNA-seq analysis also shows that Wnt5a is expressed predominantly in the lung mesenchyme at E 17.5 and at lower levels in the epithelium ( Fig.…”

Planar cell polarity regulators in asymmetric organogenesis during development and disease

“…Ror2 and Ryk differentially regulate midgut elongation through dynamic spatiotemporal interactions with Wnt5a. Mesenchyme-derived Ror2 functions before the early phase of midgut elongation, while both epithelial and mesenchymal Ryk contributes to midgut elongation throughout the early phase (Wang et al, 2020). Vangl2 regulates several polarized cell behaviors in the gut epithelium to couple epithelial morphogenesis with gut tube elongation.…”