Loss of EB2 delays mitotic progression in murine and human neural progenitors

The construction of the human brain is dependent on neuronal progenitors that divide accurately generating billions of neurons. This neurogenic potential requires the efficient assembly of the mitotic spindle, which mediates the alignment of sister chromatids and their subsequent separation. The mitotic spindle is formed from microtubules, which are decorated with proteins that alter the functional repertoire of the cytoskeleton. Mutations in EB2, a member of the end binding protein family, have been identified in individuals with multiple congenital defects including microcephaly. Here, we combine transgenic mouse models with stem cell-derived neural progenitor cultures to explore how mutations in EB2 influence embryonic brain development. We report that Eb2 is broadly expressed in the developing vertebrate brain, specifically associating with the mitotic spindle in neural progenitors. We show that a disease-causing mutation (Q152X) disrupts corticogenesis and is associated with stalling of mitosis in prometaphase, defects in chromosome congression, misaligned chromosomes and p53-induced apoptosis. Taken together, these results demonstrate that EB2 is necessary for faithful mitotic division in neural progenitors in mice and humans.