Intellectual disability-causing mutations in KIF11 impair microtubule dynamics and dendritic arborization

Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disabilities (MCLID) is a rare disease caused by mutations in the mitotic motor KIF11. However, the specific neuronal functions of KIF11, its mechanisms of microtubule (MT) regulation, and the impact of MCLID mutations on KIF11 function remain underexplored. Here, using live-imaging, we find that KIF11 depletion in postmitotic neurons increases minus-end-out MT dynamics in both axons and dendrites. Introducing MCLID-associated KIF11 mutations, KIF11Y82F and KIF11ΔCterm, significantly reduces MT dynamics, impairs dendritic arborization, and decreases mEPSC frequency. Biochemical analyses reveal that the KIF11ΔCterm mutant disrupts tetramer formation and MT crosslinking, while the KIF11Y82F mutant reduces MT sliding velocity and ATP affinity. Temporal inhibition of KIF11 using a photo-controllable KIF11 increases MT dynamics and dendritic growth. Together, these data reveal that KIF11 is a MT dynamics rheostat and regulator of dendritic arborization in mature neurons, providing essential insights into the molecular mechanisms driving MCLID. Here, the authors reveal that the mitotic motor KIF11 functions in postmitotic neurons as a microtubule-dynamics rheostat to regulate dendritic arborization. Additionally, they show how MCLID mutations impair KIF11 oligomerization, ATP hydrolysis, neuronal structure, and communication.