GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State

Abstract

Morphogen gradients require ligands to disperse across tissues from their sites of production, yet receptor engagement can consume ligand before it reaches distant cells. This poses a particular challenge for lipid-modified WNTs, whose hydrophobic palmitoleate favours ligand retention near their source and premature receptor engagement. Here we identify a palmitoleate-binding pocket in mammalian glypican-6 (GPC6), the gene mutated in the skeletal dysplasia omodysplasia, and show that shielding of the WNT5A lipid by GPC6 is required for gradient formation. Using a separation-of-function knock-in mouse allele, we demonstrate that targeted disruption of GPC6-mediated lipid shielding collapses WNT5A gradients during skeletal development by promoting premature source-proximal signalling that depletes ligand available for distal signalling. This source-proximal WNT hyperactivation engages a previously unrecognised WNT-driven RAC-PAK-MEK-ERK cascade, generating a RASopathy-like developmental state that contributes to skeletal dysplasia. Thus, GPC6 functions as a spatial gatekeeper of WNT5A utilisation, controlling the allocation of a finite ligand pool. More broadly, these findings reveal that pathway hyperactivation can arise from spatial misallocation of an endogenous signalling ligand rather than from conventional gain- or loss-of-function mutations in downstream signalling components.