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

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Microcephaly with intellectual disabilities (MCLID) is a rare genetic disorder.
• Mutations in the KIF11 gene are implicated in MCLID.
• The precise neuronal roles of KIF11 and the impact of MCLID mutations are not well understood.

Purpose of the Study:

• To investigate the function of KIF11 in mature neurons.
• To elucidate KIF11's mechanisms of microtubule (MT) regulation.
• To determine how MCLID-associated mutations affect KIF11 function and neuronal development.

Main Methods:

• Live-imaging of KIF11 function in postmitotic neurons.
• Analysis of KIF11 mutations (KIF11^Y82F and KIF11^ΔCterm) in neurons.
• Biochemical assays to assess KIF11's interaction with microtubules.
• Temporal KIF11 inhibition using photo-controllable KIF11.

Main Results:

• KIF11 depletion increases MT dynamics in axons and dendrites.
• MCLID-associated KIF11 mutations reduce MT dynamics, impair dendritic arborization, and decrease mEPSC frequency.
• KIF11^ΔCterm disrupts tetramer formation and MT crosslinking; KIF11^Y82F reduces MT sliding velocity and ATP affinity.
• Temporal KIF11 inhibition enhances MT dynamics and dendritic growth.

Conclusions:

• KIF11 acts as a rheostat controlling MT dynamics in mature neurons.
• KIF11 is crucial for regulating dendritic arborization.
• These findings provide insights into the molecular basis of MCLID.