EVC protein regulates Sonic hedgehog signaling during human intervertebral disc development and degeneration.
Wu, Zihan Shaw, Lizzy Dube, Christabel T Ionescu, Andra-Maria Qiu, Tengyang Tierney, Anna L Baird, Pauline Patel, Sonal Zeef, Leo A H Birchall, Lindsay J
Wu, Zihan
Shaw, Lizzy
Dube, Christabel T
Ionescu, Andra-Maria
Qiu, Tengyang
Tierney, Anna L
Baird, Pauline
Patel, Sonal
Zeef, Leo A H
Birchall, Lindsay J
Abstract
Notochord-derived cells (NCs) in the developing nucleus pulposus (NP) of the intervertebral disc maintain its hydrated extracellular matrix and their aging-associated loss initiates intervertebral disc degeneration, contributing to back pain. To better understand the molecular regulators of NC function, we profiled the proteome of human fetal NP cells and identified Ellis-van Creveld (EVC) protein as highly enriched in NCs. Using mouse models and CRISPR-engineered human NP cells, we show that EVC facilitates Shh signaling, supports NP cell phenotype, and limits fibrotic matrix changes. Loss of EVC reduced Gli3 processing, impaired Shh pathway activity, and altered extracellular matrix organization, while TGF-β signaling suppressed EVC expression indicating crosstalk between these pathways. These findings establish EVC as a key modulator of developmental and homeostatic signaling in the disc and suggest potential therapeutic targets for disc degeneration and fibrosis, providing strategies for preserving NP function and informing regenerative approaches.
MIDER Authors
Date
2025-12-04
Type
Article
Subject
Invertebral Disc
Collections
Citation
Wu Z, Shaw L, Dube CT, Ionescu AM, Qiu T, Tierney AL, Baird P, Patel S, Zeef LAH, Birchall LJ, Jennings RE, Hanley NA, Unwin RD, Hoyland JA, Richardson SM. EVC protein regulates Sonic hedgehog signaling during human intervertebral disc development and degeneration. iScience. 2025 Dec 4;29(1):114290. doi: 10.1016/j.isci.2025.114290.
Journal / Source Title
iScience
DOI
10.1016/j.isci.2025.114290
PMID
41550739
Publisher
Cell Press
Publisher’s URL
https://pubmed.ncbi.nlm.nih.gov/41550739/