{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Babraham Institute"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "Y. Kim"
    },
    {
      "name": "Y. Zhao"
    },
    {
      "name": "A. X. Xu"
    },
    {
      "name": "A. Nakhuda"
    },
    {
      "name": "A.-M. Androniciuc"
    },
    {
      "name": "G. Tenin"
    },
    {
      "name": "B. D. Keavney"
    },
    {
      "name": "E. Y. Jones"
    },
    {
      "affs": [
        0
      ],
      "name": "I. J. McGough"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fk7gq7eaac9p4.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.20.752969",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752969v1.full",
  "id": "fk7gq7eaac9p4",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752969v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "developmental biology"
    ],
    [
      "openalex",
      "1312|Wnt/β-catenin signaling in development and cancer"
    ]
  ],
  "openalex": "W7213969255",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752969v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-20",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fk7gq7eaac9p4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:43Z",
      "native_id": "10.64898/2026.09.20.752969",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.20.752969v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:developmental biology",
      "subfield": "developmental-biology"
    }
  ],
  "title": "GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State",
  "title_text": "GPC6 Lipid Shielding Sustains WNT5A Gradients to Prevent a RASopathy-like Developmental State",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:43Z",
  "url": "https://research.draconitic.com/paper/fk7gq7eaac9p4",
  "venue": "bioRxiv",
  "versions": []
}