Roles of mitotic kinesins, kinesin-5 and kinesin-6, in regulating neuronal migation

Aditi Falnikar

doi:10.17918/00000717

Mammalian brain development depends on migration of newborn neurons from their sites of origin to new locales. Migration of the neuron involves the extension of a leading process followed by somal translocation. According to the existing literature, cytoplasmic dynein and myosin-II, a microtubule-based motor and an actin-based motor, respectively, generate the forces that underlie neuronal migration. A variety of specialized kinesins are known to impose forces on microtubules and actin filaments during cell division, and at least two of these kinesins, namely kinesin-5 and kinesin-6, are also strongly expressed in migratory neurons which have ceased dividing. However, the functions of these mitotic motors in the migratory neuron have never been studied. Kinesin-5 is a homotetrameric motor protein, which generates forces between anti-parallel microtubules in the spindle midzone. My work shows that experimental inhibition of kinesin-5 in cultured migrating neurons results in faster moving neurons with shorter leading processes. Further, I show that short microtubules are present in the leading process and that their transport frequency is enhanced when kinesin-5 is inhibited. Conversely, overexpression of kinesin-5 in cultured migrating neurons as well as in the developing cerebral cortex causes migration to slow down. High-resolution microscopy indicates that some microtubules do not converge onto the centrosome and hence that regions of anti-parallel microtubule organization are present behind the centrosome. Kinesin-5 is enriched in these regions, suggesting them as a potential sites of action for the forces generated by this motor protein. Depleting migrating neurons of kinesin-6, a motor protein which bundles microtubules and regulates formation of actin rich cleavage furrow during cytokinesis, results in multi-polar cells that continuously change their direction of movement such that they undergo little or no net movement. Kinesin-6 normally co-localizes with actin filaments in the proximal region of the leading process. In neurons depleted of kinesin-6, microtubules undergo a change in organization, and f-actin no longer concentrates in a single process. I conclude that kinesin-5 restricts forward movement of migrating neurons by regulating microtubule-microtubule interactions, while kinesin-6 constrains process number and restricts actin-based protrusive activity to a single leading process there by ensuring directed migration.

Roles of mitotic kinesins, kinesin-5 and kinesin-6, in regulating neuronal migation

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Roles of mitotic kinesins, kinesin-5 and kinesin-6, in regulating neuronal migation

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