Mutations in one component of the minor spliceosome – which controls splicing of a small proportion of introns – have been identified as causing a number of microcephalic developmental disorders. However, the underlying cellular and molecular mechanisms leading to microcephaly are unknown. Rahul Kanadia and colleagues have now generated the first mouse model of microcephaly owing to minor spliceosome disruption and have analysed the consequences of loss of the snRNA U11 in the developing mouse pallium. They found that U11 deletion leads to radial glial cell (RGC) apoptosis, and hence depletion of the progenitor pool and reduced neuronal numbers. Moreover, RGCs show increased DNA damage, cell cycle defects and p53 upregulation. Other cell types, such as intermediate progenitors and postmitotic neurons, are relatively unaffected by the loss of U11. The authors can detect aberrant splicing of a number of targets of the minor spliceosome, and this gene set shows over-representation of cell cycle-associated functions. While further analysis is still required to dissect out the particular targets involved, and to understand the cell-type specificity of the phenotype, this mouse model should prove to be a valuable tool for the study of minor spliceosome-associated microcephaly.
