LIS1-deficient neural precursor cells (green) arrest at the nonmigratory multipolar stage in the subventricular zone.

LIS1, the protein that is affected in the developmental disorder Lissencephaly, interacts with cytoplasmic dynein in several cell systems. As neuronal positioning is disrupted by this disease, LIS1 and dynein are assumed to be involved in neuronal migration. Now, live in vivo images from Tsai et al. (page 935) reveal that migration is just one facet of LIS1 function.

Neuronal development was blocked at multiple stages following the loss of LIS1, probably depending on the efficiency of RNAi uptake in a cell. The earliest defect was seen in the proliferation of neural progenitors. The nuclei of these precursors normally oscillate in the neural tube and divide when they reach the ventricular surface. But nuclei of cells lacking LIS1 did not oscillate and never divided. The authors suspect that nuclear positioning dictates cell division in these precursors, perhaps via a mitosis-promoting signal at the ventricular surface.

LIS1-lacking neurons also stalled at the transition to a migratory bipolar state. After mitosis, differentiating neurons work their way out from the ventricles, but then pause and extend multiple processes, one of which becomes an axon and extends further. In time, the cell becomes bipolar (keeping only its axon and one migratory process) and migrates to peripheral regions of the cortex. Multipolar cells lacking LIS1, however, never converted to the expected bipolar form and remained immobile. Their axons persisted, but did not elongate like those of normal cells.

Some LIS1-lacking cells with the classic bipolar state did appear further out in the cortex. These cells were also immobile, although their migratory processes elongated normally.

The defects are probably by-products of altered dynein activity, although the specific effects of LIS1 on dynein are not well understood. Nuclear oscillation, for example, might require the linkage of nuclei via microtubules to cortical dynein/LIS1. Dynein and LIS1 are found at the leading edge of migrating fibroblasts, and the group has new evidence that they might also be in neuronal growth cones, where they could promote cell migration or axon extension.