Mice lacking two adhesion molecules (right) have smaller cerebellums.

By crossing knockout mice deficient for two cell adhesion molecules, Sakurai et al. have obtained the first genetic evidence for the molecules' functional overlap, and have explained why earlier tissue culture results were not replicated in single knockout mice (page 1259).

Sakurai and colleagues started by engineering mice deficient for NrCAM, which had only mild (∼11%) growth defects in two cerebellar lobes. When the authors crossed the NrCAM-deficient mice with existing mice that are deficient for the related cell adhesion molecule L1, the cerebellum of the double knockout was drastically reduced in size, and the mice were small and never survived later than eight days after birth. The mice probably die because their lack of coordination does not allow them to compete successfully for food.

The cerebellar defect may be largely a result of reduced migration or decreased survival of granule cells. In the double knockout, these interneurons initially differentiate and start migrating correctly, but they reach their final destination in vastly reduced numbers. There is no accumulation of these cells in other areas of the cerebellum, suggesting a survival problem.

The survival hypothesis would be consistent with tissue culture experiments, in which Sakurai et al. added L1 antibodies to cells isolated from NrCAM-deficient mice, and observed a dramatic reduction in viability at around day 14 of culture. More experiments along these lines should reveal the specific functions of L1, NrCAM, and the two other related CAMs (neurofascin and CHL1) in processes such as cell migration, axon bundling, and synaptogenesis. ▪