GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State
- 1Babraham Institute
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.
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BibTeX
@misc{kim2026gpc6,
title = {{GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State}},
author = {Y. Kim and Y. Zhao and A. X. Xu and A. Nakhuda and A.-M. Androniciuc and G. Tenin and B. D. Keavney and E. Y. Jones and I. J. McGough},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.752969},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.752969v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State
AU - Y. Kim
AU - Y. Zhao
AU - A. X. Xu
AU - A. Nakhuda
AU - A.-M. Androniciuc
AU - G. Tenin
AU - B. D. Keavney
AU - E. Y. Jones
AU - I. J. McGough
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.752969
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.752969v1
AB - 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.
ER -