# EVC protein regulates Sonic hedgehog signaling during human intervertebral disc development and degeneration

## TL;DR

This study shows that EVC protein helps regulate cell signaling in spinal discs, maintaining their structure and preventing degeneration.

## Contribution

The study identifies EVC as a novel regulator of Sonic hedgehog signaling in human intervertebral disc development and degeneration.

## Key findings

- EVC is highly enriched in notochord-derived cells of the nucleus pulposus.
- EVC supports NP cell phenotype and limits fibrotic matrix changes by regulating Shh signaling.
- TGF-β signaling suppresses EVC expression, indicating pathway crosstalk.

## 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.

•EVC protein is enriched in human fetal notochord-derived cells of the nucleus pulposus•EVC positively regulates Shh signaling in nucleus pulposus cells•EVC and Shh pathway maintain NP cell phenotype and reduce fibrosis•TGF-β signaling downregulates EVC expression

EVC protein is enriched in human fetal notochord-derived cells of the nucleus pulposus

EVC positively regulates Shh signaling in nucleus pulposus cells

EVC and Shh pathway maintain NP cell phenotype and reduce fibrosis

TGF-β signaling downregulates EVC expression

Development; Matrix biology; Cilium biology; Signaling