Ca 2+ -mediated protein citrullination regulates proliferation in the regenerating and malignant CNS

Summary Unlike most adult mammals, regenerative vertebrates can awaken dormant neural stem cells in response to injury. Understanding how this process is regulated could guide strategies to activate stem cells for tissue repair and limit aberrant proliferation in cancers of the CNS. Here, using zebrafish injury models and high-speed live imaging, we identify hydrodynamically-activated Ca²⁺ signalling as a key driver of neural stem cell activation. Local injury-associated changes in CSF flow activate mechanoreceptors at the site of spinal cord lesions, triggering pulsatile Ca²⁺ activity and progenitor proliferation. We identify Ca²⁺-regulated peptidylarginine deiminase enzymes (PADs) as key downstream effectors that citrullinate intracellular targets in a Ca²⁺-dependent manner to drive progenitor activation. Finally, we show that PAD inhibitors suppress the growth of aggressive medulloblastoma cells in preclinical laboratory models. Together, these findings uncover a novel mechanism of proliferation control in the vertebrate CNS and highlight the value of regenerative studies for identifying therapeutic targets. Graphical Summary Highlights Damage signals trigger changes in cilia activity and CSF flow to create a transient hydrodynamic niche at the site of spinal cord injuries. Specialised CSF-contacting neurons detect altered CSF circulation and initiate a signalling relay that culminates in elevated Ca²⁺ activity within dormant neural progenitors. Ca²⁺-activated PAD enzymes link Ca²⁺ signalling to cell cycle progression by citrullinating intracellular targets in a Ca²⁺-dependent manner. PAD inhibition suppresses medulloblastoma growth in preclinical laboratory models, revealing a conserved regulatory mechanism with translational potential.