Ca2+-mediated protein citrullination regulates proliferation in the regenerating and malignant CNS

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 Ca{superscript 2} 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 Ca{superscript 2} activity and progenitor proliferation. We identify Ca{superscript 2}-regulated peptidylarginine deiminase enzymes (PADs) as key downstream effectors that citrullinate intracellular targets in a Ca{superscript 2}-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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/701650v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@3b7a56org.highwire.dtl.DTLVardef@dcc81forg.highwire.dtl.DTLVardef@d6a208org.highwire.dtl.DTLVardef@127de86_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDamage signals trigger changes in cilia activity and CSF flow to create a transient hydrodynamic niche at the site of spinal cord injuries. C_LIO_LISpecialised CSF-contacting neurons detect altered CSF circulation and initiate a signalling relay that culminates in elevated Ca{superscript 2} activity within dormant neural progenitors. C_LIO_LICa{superscript 2}-activated PAD enzymes link Ca{superscript 2} signalling to cell cycle progression by citrullinating intracellular targets in a Ca{superscript 2}-dependent manner. C_LIO_LIPAD inhibition suppresses medulloblastoma growth in preclinical laboratory models, revealing a conserved regulatory mechanism with translational potential. C_LI