The brain is our information processing centre responsible for higher cognitive functions, such as language, memory and thought. Development of this highly complex structure requires coordinated control of neural stem cell expansion, nerve cell specification, migration and integration in neuronal circuitries. Disturbance of any of these processes has been linked to a variety of neurodevelopmental disorders, including common disorders such as autism and intellectual disability (ID). ID, which affects 1-3% of the population, can be classified based on IQ score as mild, moderate, severe or profound and can occur in isolation or as part of a developmental syndrome in which also other organs and systems are affected. Individuals often require life-long care, exhibit behavioural problems and have a reduced quality of life.
In most cases, ID is caused by a gene mutation, i.e. the DNA of the patient is altered at a specific location. These mutations often arise spontaneously prior to or shortly after fertilization and cause the affected gene to malfunction. To date, alterations in around 700 different genes have been linked to ID, but it remains unclear when, where and why malfunction of these genes results in cognitive impairment. In addition, it is thought that mutations in many more, not yet identified genes can cause ID. To provide patients and their families with the most accurate diagnosis, prognosis and treatment plan, it is important to be able to accurately pinpoint the causative gene mutation. In addition, recent studies suggest that some aspects of neurodevelopmental disorders may be treatable by drug intervention. Memory defects, repetitive behaviour and seizures were all reduced upon drug treatment in animal models of human disorders, suggesting that such a therapeutic avenue could have important consequences for the quality of life of ID patients.
For a better, faster diagnosis and potential treatment, it is important that we understand which developmental processes and which cells are affected by ID-causing gene mutations. Until recently, it was difficult to study these processes due to lack of an appropriate model system for human brain development. This has changed with the enormous progress that has been made in growing human brain organoids from pluripotent stem cells. These three-dimensional (3D) structures, also called ‘mini-brains’, generate similar cell types along a comparable timeline to embryonic and fetal human brains and thus can be used to study the effects of disease-causing mutations.
In our work, we focused on two genes, NIPBL and INTS8. Mutations in these genes cause related neurodevelopmental disorders, where patients display moderate to severe cognitive delay, seizures and difficulty communicating. We generated human neural stem cells and 3D brain organoids from cells in which NIPBL and INTS8 were mutated and used these to identify the misregulated pathways that can contribute to symptoms displayed by patients.
