Kinesin Regulation in the Proximal Axon is Essential for Dendrite-selective Transport

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Neurons exhibit distinct polarity, with dendrites receiving signals and axons transmitting them.
• Maintaining this polarity requires precise regulation of intracellular transport, particularly for proteins destined for specific neuronal compartments.

Purpose of the Study:

• To investigate the role of kinesin regulation in terminating anterograde axonal transport of dendrite-selective vesicles.
• To elucidate the mechanism by which neuronal polarity is maintained at the axon entry point.

Main Methods:

• Overexpression of the dendrite-selective kinesin KIF13A in neurons.
• Co-expression of the kinase MARK2/Par1b with KIF13A.
• Investigation of KIF13A interactions with 14-3-3 isoforms.
• Treatment with small molecule inhibitors of MARK2 and 14-3-3.

Main Results:

• Overexpressing KIF13A led to mistargeting of dendrite-selective vesicles into the axon and loss of neuronal polarity.
• Co-expression of MARK2/Par1b prevented this polarity loss.
• MARK2/Par1b phosphorylates KIF13A at a specific site, facilitating binding to 14-3-3 proteins (14-3-3β and 14-3-3ζ).
• Inhibition of MARK2 or 14-3-3 activity disrupted neuronal polarity.

Conclusions:

• Kinesin regulation, specifically MARK2-mediated phosphorylation of KIF13A, is crucial for maintaining dendrite-selective vesicle transport.
• A novel model proposes that MARK2-dependent phosphorylation of KIF13A leads to 14-3-3 binding, terminating transport and restricting vesicles from the axon.
• This mechanism represents a new paradigm for regulating vesicle transport via localized kinesin tail phosphorylation to maintain neuronal polarity.