A protein that's defective in patients with reduced brain size helps prevent untimely chromosome condensation, Yamashita et al. show.
Babies born with autosomal recessive primary microcephaly have an abnormally small brain and learning difficulties. Several faulty genes can trigger this condition, including mutated versions of MCPH1. A clue to MCPH1’s function came when researchers noticed that cells from patients with defective versions of the gene undergo premature chromosome condensation (PCC), in which the chromosomes compact during G2. That observation suggested that MCPH1 mutations trigger the early activation of condensin II, a protein complex that promotes chromosome condensation during prophase.
Yamashita et al. tested that idea in Xenopus egg extracts. They found that human MCPH1 prevents condensin II from settling on chromosomes, a necessary step in order to initiate their condensation. In contrast, MCPH1 had no effect on two other proteins that foster chromosome condensation, condensin I and topoisomerase II. The researchers showed that the N terminus of MCPH1 blocks condensin II by competing with it for binding sites on the chromosomes. The team also determined that two mutations found in primary microcephaly patients reduce MCPH1’s ability to hamper condensin II.
Those results suggest that MCPH1 regulates chromosome condensation by directly inhibiting condensin II. But how MCPH1 mutations cause microcephaly remains unclear. PCC doesn't kill cells—they can even undergo mitosis. MCPH1 and its relatives congregate on centrosomes, and the researchers speculate that the mutations weaken interactions between the centrosome and the nucleus that are necessary for the unique form of cell division that occurs during neurogenesis.