The role of microtubule-associated motors and crosslinkers in neurodevelopment

Shrobona Guha

doi:10.17918/00010847

It is a truth universally acknowledged that cellular structural changes must result from modifications to the underlying cytoskeleton. With the help of the microtubule cytoskeleton, specialized cells like neurons undergo major structural rearrangements to perform their designated functions at each stage of development. The microtubules also act like a railroad, allowing the transport of cargo like mitochondria by motor proteins such as dynein and kinesins. Although our understanding of these proteins mainly comes from mitosis, mitotic motors have been repurposed to have important roles in organizing the microtubule cytoskeleton in postmitotic neurons. Our studies on neurons cultured from the central nervous system (CNS) reveal that dynein is assisted by kinesin-1, crosslinker TRIM46, and the augmin complex in establishing the plus-end-out microtubule polarity of axons. However, for peripheral neurons, the mechanism is primarily dynein-based, with kinesin-1, TRIM46, or augmin depletion not affecting the polarity pattern. The kinesin required for both CNS and PNS axonal microtubule organization is uncharacteristic kinesin KIFC1. KIFC1 is a minus-end-directed kinesin that crosslinks and slides microtubules, and KIFC1-depleted neurons show defective growth cones, resulting in shorter axons with loss of the plus-end-out microtubule polarity orientation. KIFC1-driven microtubule crosslinking and sliding are also employed by the neuron during neurogenesis and dendrite formation. For our studies, in vitro cell culture and developing mouse brains in vivo, along with RNA interference techniques, were used to delve into KIFC1's functions. During neurogenesis, forces exerted by KIFC1 on the microtubules around the nucleus are responsible for the nuclear movements necessary for the differentiation and subsequent migration of newborn neurons. KIFC1-depleted neurons lag in reaching their appropriate cortical layer due to failure in maintaining the trajectory. Once the neuron matures, KIFC1 crosslinks the dendritic minus-end out microtubules in place and prevents them from sliding back into the cell body. Acute pharmacological inhibition of KIFC1 has adverse effects on dendritic structure as well as the density and morphology of dendritic spines. Together, these results reveal that KIFC1 plays multiple roles during neurodevelopment. Finally, our studies conclude that the organization of the microtubule cytoskeleton by motor proteins is crucial for the formation of the nervous system.

The role of microtubule-associated motors and crosslinkers in neurodevelopment

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The role of microtubule-associated motors and crosslinkers in neurodevelopment

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