GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State
En palabras de los autores
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.
Apareció: miércoles, 23 de septiembre. bioRxiv. Preprint, todavía sin revisión por pares.