Loss of one allele of the LIS1 gene causes lissencephaly, a developmental disorder that affects cortical neuron migration, giving the brain surface a smooth appearance. LIS1 is a subunit of platelet-activating-factor acetyl hydrolase. However, this insight has not explained how LIS1 function is related so exquisitely to cortical development. Now, three papers in Nature Cell Biology indicate that the link between this protein and lissencephaly may be related instead to the interaction of LIS1 with the microtubule motor dynein.

Dynein participates in cell division as well as in different forms of cellular transport. These papers report a physical interaction between LIS1 and dynein and provide evidence for the regulation of microtubule transport by LIS1. Furthermore, changes in the levels of this protein interfere with mitosis and, in Drosophila melanogaster neurons, lead to shorter dendrites and abnormal axonal transport.

These findings raise the possibility that LIS1 affects neuronal migration by interfering directly with cytoskeletal dynamics or, alternatively, by reducing the number of migratory cells through its effect on mitosis. Either way, it is likely that this lead will be a smoother path to follow in our understanding of smooth brains.