Kinesin‐12 (Kif15) in Neurons: From Mitotic Motor to Activity‐Dependent Regulator of Dendritic Spines

ABSTRACT Kinesin‐12 (Kif15) is a canonical mitotic kinesin that crosslinks parallel microtubules and suppresses microtubule catastrophe. It exists in both dimeric and tetrameric oligomerization states that are regulated by ionic conditions and binding partners. Its persistent expression in postmitotic neurons indicates that this ancestral microtubule‐organizing activity has been repurposed for neuronal functions, yet the dendritic role of Kif15 has remained poorly defined. Here, we review and hypothesize KIF15 acting as a dendritic regulator. We propose that in the dendritic shaft, Kif15 exists predominantly as a tetramer crosslinker to organize the mixed‐polarity antiparallel microtubule array. At the neck of the dendritic spines, perhaps due to the electrical signals, the compartmental ion concentration has changed. The dimeric Kif15 transports PSD95 along microtubule plus ends that invade dendritic spines and unloads PSD95 at the postsynaptic sites. There, synaptic activity triggers Ca 2+ influx and CaMKII activation to promote Kif15 association with Myosin IIb (Myh10), forming a Kif15‐Myh10 hetero‐complex, which reorganizes the microtubule–actin network to facilitate mushroom‐like dendritic spine formation. This framework explains why Kif15 loss impairs spine complexity, synaptic development, and mood‐related behaviors without causing catastrophic disassembly of dendritic microtubules. It further links KIF15 mutations to cognitive disorders and suggests that mechanistic insights from a mitotic motor to its synaptic functions.