Rapid elongation of the murine midgut is driven by active proliferation. During this time, pseudostratified midgut epithelial cells undergo interkinetic nuclear migration, whereby their nuclei move apically before dividing. It is known that the subsequent post-mitotic movement of daughter nuclei basally is guided by WNT5A secreted by the underlying mesenchyme, but how epithelial cells detect and respond to mesenchymal WNT5A is unknown. Now, Terry Lechler, Deborah Gumucio and colleagues show that the WNT5A receptor RYK plays a key role in this process. They first reveal that, while the WNT5A receptor ROR2 is expressed in both epithelial and mesenchymal cells, epithelial ROR2 is dispensable for gut elongation. By contrast, RYK is required; Ryk−/− embryos exhibit a significant reduction in midgut length. Furthermore, RYK is essential for the proper basal re-connection of postmitotic epithelial cells. Specifically, in the absence of Ryk, some midgut epithelial cells fail to extend stable filopodial protrusions basally to form a path along which their nuclei can return, mimicking the defects observed in Wnt5a−/− midguts. Finally, the authors show that failure of this pathfinding process leads to apoptosis, which – based on computational modelling – accounts for the diminished midgut elongation seen in Ryk mutants. Together, these findings highlight that WNT5A-RYK acts as a navigation system to instruct filopodial pathfinding in the midgut.
WNT5A-RYK signalling: the path to fetal gut elongation
WNT5A-RYK signalling: the path to fetal gut elongation. Development 15 October 2020; 147 (20): e2002. doi:
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