The pyramidal cell layer is fractured in a-tubulin mutant mice. Image courtesy of Dr. David Keays, Wellcome Trust Centre for Human Genetics, University of Oxford.
Neurons, like rental cars, would benefit from global positioning systems. Precise neuronal migration in development is necessary for proper neuronal function in the adult. Lissencephaly is a neuronal migration disorder that causes the brain to appear 'smooth', lacking gyri and sulci, and results in cognitive and motor impairment. Keays et al. report mutations in 
-tubulin in mice with deficits in neuronal migration and in people with type 1 lissencephaly in a recent article in Cell.
The authors did a high-throughput, forward-genetic screen for hyperactivity in the mouse. They screened 9216 of the offspring from normal female mice and male mice injected with N-ethyl-N-nitrosourea (ENU), which randomly mutates sperm. They identified a dominant phenotype that mapped to a point mutation in -1 tubulin (Tuba1) that caused a serine to glycine substitution at amino acid 140 (S140G).
Amino acid 140 lies in the guanosine triphosphate (GTP)-binding pocket of -tubulin. GTP is a cofactor required for the formation of - and 
-tubulin heterodimers, which are the building blocks for microtubules. S140G -tubulin showed reduced GTP binding and / tubulin dimerization relative to wild-type -tubulin.
Mice with the S140G mutation in -tubulin showed unusual hippocampal and cortical lamination. In the hippocampus, the pyramidal cell layer was split in half, with two layers of pyramidal cells located side by side. Calbindin immunocytochemistry showed fewer pyramidal cells in CA1 and disorganization of the mossy fiber tract that extends from dentate gyrus to CA3 neurons in mutant relative to wild-type mice. Unlike the wild-type cortex, NeuN-labeled neurons in layer IV of the mutant cortex were organized in three or four horizontal tracts.
Bromodeoxyuridine (BrdU) labels DNA in dividing neurons. Neurons in layer IV of the cortex and the pyramidal cell layer of the hippocampus are born on approximately embryonic day 14.5. Relative to wild-type mice, S140G -tubulin mice injected with BrdU on embryonic day 14.5 showed fewer BrdU-positive neurons in outer layers of the cortex and had more disorganized hippocampi on the day of birth. The authors believe that deficits in neuronal migration result in the unusual morphology in the adult brain in S140G -tubulin mice.
S140G -tubulin mice showed behavioral deficits consistent with hippocampal impairment. The authors tested hippocampus-dependent working memory by alternating the goal arm in a T-maze. Unlike wild-type mice, -tubulin mutant mice did not learn to alternate arms. In contrast, hippocampus-independent behaviors were normal in S140G -tubulin mice. For example, both wild-type and mutant mice learned to associate surface textures with rewards.
Type 1 lissencephaly associates with mutations in doublecortin and Lis1, and mice with mutations in these genes show deficits in neuronal migration and cognitive behaviors. The authors identified mutations in the human homolog of -1 tubulin, TUBA3, in two people with type 1 lissencaphaly who did not have mutations in doublecortin or Lis1. They also found TUBA3 mutations in six people with other cortical defects. Together, these data suggest that mutations in tubulin genes cause some types of lissencephaly and may also cause other disorders of cortical development.