Research: Line up

Mouse models shed light on the genetic basis of human developmental disorders.

Ordered neuronal migration is an essential part of brain development. As such, mutations that affect this process can produce brain defects and behavioural problems in humans and animals.

To investigate the genes involved in these disorders, an international team including David Keays and Jonathan Flint from the Wellcome Trust Centre for Human Genetics, Oxford, used a mutagen, ethylnitrosurea (ENU), to generate lines of mice with randomly acquired mutations. The researchers then screened for animals showing neurological or behavioural abnormalities.

One mouse mutant, with brain abnormalities and impaired neuronal migration, had acquired a mutation in a protein called alpha-1 tubulin (Tuba1). The mutation prevents alpha-1 tubulin from binding guanosine triphosphate (GTP), a chemical vital for the assembly of tubulin into microtubules – components of the cell internal skeleton known to be important in cell migration.

These mice mutants had similar physical characteristics to mouse models of a human disease called lissencephaly (where some or all of the brain's surface is smooth, instead of folded). This prompted the team to screen a group of people with developmental abnormalities. They found mutations in TUBA3, the human equivalent of Tuba1, in two individuals.

The work highlights the ability of ENU-based screens in mice to identify mutations corresponding to diseasecausing mutations in people.

External links

• Keays DA et al. Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 2007;128(1):45–57.