Role of kinesin-5 in neuronal migration

Vertebrate brain development depends on the migration of neurons from their birthplaces to new locales. Flaws in neuronal migration lead to abnormal brain lamination, underlying developmental disorders such as lissencephaly.  Kinesin-5, a homotetrameric motor protein that interacts with adjacent anti-parallel microtubules during mitosis, continues to be expressed in postmitotic migratory neurons.  Here we show that expression of kinesin-5 is strongest when migration ceases.  Inhibition of kinesin-5 results in faster-moving neurons with shorter leading processes.  In addition, the directionality of migration is more random, the distance between the centrosome and the nucleus is shorter, and the frequency of short microtubule (MT) transport within the leading process is enhanced.  By contrast, kinesin-5 overexpression causes migration to cease.  Electron tomographic analyses revealed that many of the longer MTs extending into the leading process are not attached to the centrosome but rather extend behind it, thus intermingling with MTs of the opposite orientation.  Such regions of anti-parallel MTs are ideally suited for kinesin-5-based forces to act as a brake to slow neuronal migration, and these regions immunostain strongly for kinesin-5.  Our results support a model in which the forces generated by kinesin-5 critically influence the rate and directionality of neuronal migration, and ultimately contribute to its cessation.  In support of this model, a mild overexpression of kinesin-5 in embryonic mouse brain (using in utero electroporation) slowed the rate of neuronal migration.  These findings highlight kinesin-5 as an appealing candidate for the molecular switch that stops neurons from migrating once they have reached their destinations.