Molecular mechanisms of the Ca2+/Calmodulin-mediated control of actin cytoskeleton-driven neuromorphogenesis processes mediated by the actin nucleator JMY

Local formation of actin filaments powers neuronal morphology development and plasticity. Yet, responsible actin nucleators and their linkage to calcium transients largely remained elusive. Gain-offunction and loss-of-function studies unravel that JMY (Junction-mediating and regulatory protein) – a WH2 domain-based actin nucleator – promotes dendritic arborization and extension. This crucial function reflects JMY’s ability to promote actin filament formation, as it depended on JMY’s Arp2/3 complex coupling, Arp2/3 complex activity and presence and functionality of JMY’s WH2 domains. Importantly, WH2 domain #1 showed the tightest actin association and was regulated by the calcium sensor protein calmodulin in a reversible manner. Deletion of the calmodulin binding site or impairing actin binding of WH2 domain #1 rendered JMY dysfunctional. In line, JMY-mediated dendritic arborization relied on proper Ca2+/calmodulin signaling. Together, these results strongly suggests that Ca2+/calmodulin-control represents a thus far underrecognized, general principle for regulating actin nucleation underlying neuromorphogenesis indispensable for proper neuronal network formation.