The kinesin I family of motor proteins are crucial for axonal transport, but their roles in dendritic transport and postsynaptic function are not well-defined. Gene duplication and subsequent diversification give rise to three homologous kinesin I proteins (KIF5A, KIF5B and KIF5C) in vertebrates, but it is not clear whether and how they exhibit functional specificity. Here we show that knockdown of KIF5A or KIF5B differentially affects excitatory synapses and dendritic transport in hippocampal neurons. The functional specificities of the two kinesins are determined by their diverse carboxyl-termini, where arginine methylation occurs in KIF5B and regulates its function. KIF5B conditional knockout mice exhibit deficits in dendritic spine morphogenesis, synaptic plasticity and memory formation. Our findings provide insights into how expansion of the kinesin I family during evolution leads to diversification and specialization of motor proteins in regulating postsynaptic function.
Keywords: cell biology; dendritic spine; intracellular transport; learning and memory; mouse; neuroscience; post-translational modification; rat; synapse.
Transporting molecules within a cell becomes a daunting task when the cell is a neuron, with fibers called axons and dendrites that can stretch as long as a meter. Neurons use many different molecules to send messages across the body and store memories in the brain. If the right molecules cannot be delivered along the length of nerve cells, connections to neighboring neurons may decay, which may impair learning and memory. Motor proteins are responsible for transporting molecules within cells. Kinesins are a type of motor protein that typically transports materials from the body of a neuron to the cell’s periphery, including the dendrites, which is where a neuron receives messages from other nerve cells. Each cell has up to 45 different kinesin motors, but it is not known whether each one performs a distinct task or if they have overlapping roles. Now, Zhao, Fok et al. have studied two similar kinesins, called KIF5A and KIF5B, in rodent neurons to determine their roles. First, it was shown that both proteins were found at dendritic spines, which are small outgrowths on dendrites where contact with other cells occurs. Next, KIF5A and KIF5B were depleted, one at a time, from neurons extracted from a brain region called the hippocampus. Removing KIF5B interfered with the formation of dendritic spines, but removing KIF5A did not have an effect. Dendritic spines are essential for learning and memory, so several behavioral tests were conducted on mice that had been genetically modified to express less KIF5B in the forebrain. These tests revealed that the mice performed poorly in tasks that tested their memory recall. This work opens a new area of research studying the specific roles of different kinesin motor proteins in nerve cells. This could have important implications because certain kinesin motor proteins such as KIF5A are known to be defective in some inherited neurodegenerative diseases.
© 2020, Zhao et al.