In this issue on page 551, Silver and colleagues report a surprising regulator of neural stem cell mitosis and brain size in mice and investigate how its disruption might lead to microcephaly.

In a previous mutagenesis screen, the authors had isolated a mutant mouse with a small body size, hypopigmentation and a reduced brain size. Here they identify Magoh as a candidate gene responsible for the microcephalic phenotype. The Magoh gene, which is completely conserved between mice and humans, encodes a component of the RNA-binding exon junction complex (EJC). Mice homozygous for the Magoh loss-of-function mutation died prenatally, whereas the brains of adult mice heterozygous for the mutation showed disordered cortical layering and fewer neurons as compared with wild-type mice. The figure shows wild-type embryonic day 16.5 (E16.5) cortex, with Tbr2 (red) labeling intermediate progenitors, BrdU (green) indicating proliferating cells and DAPI (blue) staining all nuclei. Dividing intermediate progenitors appear yellow. In the Magoh mutant cortex, the number of dividing intermediate progenitors was reduced from E12.5 onwards, whereas the numbers of cells expressing immature neuron markers were increased. The prematurely born neurons, however, did not survive by E18.5.

How does an EJC component maintain the intermediate progenitor pool and prevent precocious neurogenesis? Dividing cells in the Magoh mutants had altered mitotic spindle orientations and aberrant chromosome numbers, a phenotype similar to that of Lis1 mutant mice. Lis1 encodes a microtubule-associated protein that is critical for mitotic spindle integrity; in humans, altered LIS1 dosages have been associated with microcephaly syndromes. Lis1 protein levels were decreased in the Magoh mutant cortex. Critically, Silver et al. rescued the Magoh microcephaly phenotype with Lis1 expression. By finding that Magoh controls neural stem cell division by regulating levels of Lis1 protein, Silver and colleagues have identified a new role for the EJC in determining brain size.