Role of kinesin-5 in growth cone behavior

Vidya C. Nadar

doi:10.17918/00009415

The growth cone at the tip of the axon is essential for guiding the axon during development to its appropriate target. Growth cones can be divided into a microtubule-rich central (C-) domain, an actin-rich peripheral (P-) domain and the transition (T-) zone between them. Polarized rearrangement of cytoskeletal elements in the growth cone underlies its turning toward or away from environmental cues. Growth cone turning requires selective invasion of microtubules from the C-domain into the P-domain in the direction of the cue. Studies to date have attributed this invasion to the dynamic properties of the microtubules. I have tested another idea, specifically that molecular motors involved in organizing microtubules in the mitotic spindle play a critical role in regulating the polarized distribution of microtubules during growth cone turning. This idea builds on observations that the invasion of microtubules into the P-domain is determined by a tug-of-war between forces exerted by cytoplasmic dynein and myosin-II. I hypothesized that kinesin-5, a motor that counterbalances dynein-based forces during mitosis, tips the balance of forces in a polarized fashion within growth cones, to elicit the selective invasion of microtubules into the appropriate side of the growth cone during turning. I observed that depletion of kinesin-5 or pharmacologic inhibition of kinesin-5 inhibited growth cone turning in response to environmental cues. Kinesin-5 is enriched in the T-zone, where the phospho-kinesin-5 polarizes away from the direction of turning. Experiments with non-phosphorylatable kinesin-5 resulted in increased microtubule invasion and lack of growth cone turning, similar to depletion or inhibition of kinesin-5, indicating that phosphorylation regulates kinesin-5 function in the growth cone. This provides an attractive means by which signaling pathways relevant to growth cone turning could utilize kinesin-5 to polarize the microtubule array. As a test of the feasibility of this idea, I used micro-CALI to locally inactivate kinesin-5 in different domains of the growth cone, and found that local inactivation specifically in the T-zone results in increased invasion of microtubules into the P-domain. I conclude that kinesin-5 functions in the T-zone of growth cones to regulate growth cone turning and kinesin-5 function is regulated by phosphorylation.

Role of kinesin-5 in growth cone behavior

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Role of kinesin-5 in growth cone behavior

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