Editor's evaluation: Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model

Abstract

During development, a complex network of genes ensures that the brain develops in the right way. In particular, they control how special ‘progenitor’ cells multiply and mature to form neurons during a process known as neurogenesis. Genetic mutations that interfere with neurogenesis can lead to disability and defects such as microcephaly, where children are born with abnormally small brains. DDX3X syndrome is a recently identified condition characterised by intellectual disability, delayed acquisition of movement and language skills, low muscle tone and, frequently, a diagnosis of autism spectrum disorder. It emerges when certain mutations are present in the DDX3X gene, which helps to control the process by which proteins are built in a cell (also known as translation). The syndrome affects girls more often than boys, potentially because DDX3X is carried on the X chromosome. Many of the disease-causing mutations in the DDX3X gene also reduce the levels of DDX3X protein. However, exactly what genes DDX3X controls and how its loss impairs brain development remain poorly understood. To address this problem, Hoye et al. set out to investigate the role of Ddx3x in mice neurogenesis. Experiments with genetically altered mice confirmed that complete loss of the gene indeed caused severe reduction in brain size at birth; just as in humans with mild microcephaly, this was only present in affected females. Further genetic studies revealed the reason for this: the closely related Ddx3y gene, which is only present on the Y (male) chromosome, helped to compensate for the loss of Ddx3x in the male mice. Next, the effect of the loss of just one copy of Ddx3x on neurogenesis was examined by following how progenitor cells developed. This likely reflects DDX3X levels in patients with the syndrome. Loss of the gene made the cells divide more slowly and produce fewer mature nerve cells, suggesting that smaller brain size and brain malformations caused by mutations in DDX3X could be due to impaired neurogenesis. Finally, a set of further biochemical and genetic experiments revealed a key set of genes that are under the control of the DDX3X protein. These results shed new light on how a molecular actor which helps to control translation is a key part of normal brain development. This understanding could one day help improve clinical management or treatments for DDX3X syndrome and related neurological disorders.