A large family with some members that have a rare brain disorder has helped scientists learn more about both brain development and a signaling antenna that's present on many types of cells called the primary cilium. This work, which has been reported in Nature Communications, has provided new insight into the regulation of cerebral cortex development. This region of the brain has been linked to awareness and perception, thought, language, and consciousness.
Children in this family have primary microcephaly, a disorder in which the size of the cerebral cortex is reduced, and cognitive dysfunction results to varying degrees. The children with the disorder were found to be carrying genetic mutations in both copies of a gene called RRP7A (the mutations were homozygous).
In this work, the researchers used stem cells as well as a zebrafish model to analyze the impact of these mutations. Their work showed that RRP7A is critical for the formation and proliferation of neurons during development, which can explain why mutations in the gene can have such profound consequences. It may also show why the brain is affected by the mutations while other tissues remain unperturbed.
"Our discovery is surprising because it reveals hitherto unknown mechanisms involved in the development of the brain. In addition, it highlights the value of research in rare disorders, which is important both for the patients and family affected by the disease but also beneficial for society in the form of new knowledge about human biology," said study author and Professor Lars Allan Larsen of the Department of Cellular and Molecular Medicine at the University of Copenhagen (UCPH).
The RRP7A mutations were found to disrupt the function of a structure non the surface of cells that is crucial for cell signaling and sensing the cellular environment, called the primary cilium. Cilia are also involved in the growth of new neurons. Mutations in genes that affect primary cilia are called ciliopathies, and brain disorders are a feature of several of them.
"Our results open a new avenue for understanding how primary cilia control developmental processes, and how certain mutations at these antenna-like structures compromise the formation of tissues and organs during development. To this end, we have already initiated a series of investigations to understand the mechanisms by which RRP7A regulates ciliary signaling to control formation and organization of neurons in the brain, and how defects in this signaling may lead to brain malformation and cognitive disorders," said Professor Søren Tvorup Christensen of the Department of Biology at UCPH.