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

Abstract

Precise control of axonal and dendritic architecture is vital for proper brain function, with microtubule (MT) dynamics playing a central role in this process. Here, we uncover a previously unrecognized function of the molecular motor protein KIF11, which acts as a MT dynamics rheostat in hippocampal neurons to modulate dendritic branching. Known for its role in mitotic spindle bipolarity, KIF11 is also implicated in Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disabilities (MCLID). However, the specific neuronal functions of KIF11 and the impact of its mutations in MCLID have remained largely unexplored. Our studies, using quantitative imaging of MT dynamics following KIF11 inhibition, indicate that KIF11 preferentially binds to parallel MTs in mature neurons. This binding is associated with a marked increase in minus-end-out MT dynamics in both axons and dendrites upon KIF11 loss of function, coupled with enhanced MT flux and extended growth in tertiary dendrites. These changes suggest a novel role for KIF11 in orchestrating dendritic branching. Moreover, introducing MCLID-associated KIF11 mutations, KIF11Y82F, and KIF11{Delta}Cterm, which cause minor microcephaly but severe intellectual disabilities, leads to significantly reduced MT dynamics and impaired dendritic arborization. In a microtubule sliding assay, KIF11Y82F significantly reduced KIF11 velocity while KIF11{Delta}Cterm increased it. Temporal inhibition of KIF11 using a photo-inhibitable KIF11, show increased MT dynamics and dendritic growth, while activation results in kinked and twisted branches. Together, these data reveal that KIF11 is MT dynamics rheostat and regulator of dendritic arborization in mature neurons and provide new insights into the molecular mechanisms driving MCLID.