Mutations affecting tubulin genes have been implicated in a range of human neurological disorders but very little is known about the cellular mechanisms that underlie these disorders. Now, on p. 1126, David Keays and co-workers examine how a mutation in the murine homologue of TUBB5 leads to a disease phenotype. Using two new mouse models – a conditional Tubb5 E401K knock-in (which mimics a human mutation) and a conditional knockout – they reveal that Tubb5 perturbation causes a decrease in brain size in mice, mimicking the microcephaly phenotype described in patients with TUBB5 mutations. Although the laminar structure of the cortex is largely maintained in mutants, a loss of upper neuronal layers is seen. The authors further reveal that Tubb5 perturbation causes defects in mitotic progression that lead to massive apoptosis in the brain; in line with this, increased levels of the apoptotic driver p53 are observed. Finally, the researchers note that ectopic progenitors and spindle orientation defects are observed in Tubb5 E401K mutants but not knockout mice, suggesting that the E401K mutation acts via a complex mechanism. Together, these results provide key insights into the pathology underlying tubulin-associated diseases.
TUBB5 analysis yields insights into microcephaly
TUBB5 analysis yields insights into microcephaly. Development 1 April 2016; 143 (7): e0701. doi:
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