Researchers in the Brain Research Center (BRC) at NYCU investigates mechanisms brain functions and discover potential treatments to brain disorders. In Taiwan, there are approximately 200,000 patients with epilepsy or brain developmental disorders. These patients face challenges due to their mental, physical, and mental disabilities when they try to live independently and work.

Mosaic radial glia cells

Based on the experience in studying the development of the brain, researchers at the BRC developed the first gene screening method that combined transposition with in utero electroporation, a technique to allow the induction of mutations in neural stem cells. Using this method, the screening for genes that are important during neuronal development was possible and the team has identified many new genes that are involved in brain development and neural diseases. In addition, by cooperating with the Genomics Research Center of NYCU, and the epilepsy surgery team of Taipei Veterans General Hospital, the team has been able to carry out clinical verification of these genes. With “Next Generation Sequencing,” the team was able to verify that a mutated gene found in mice is also present in patients with focal corticaldysplsia and epilepsy.

Researchers at NYCU has also been investigating other related brain developmental disorders in collaboration with international scientists to discover the mechanism behind brain malignant tumors. To understand the mechanism of medulloblastoma, the most common deadly malignant childhood brain tumor, the team and a French team at the Curie Institute used cerebellar electroporation and successfully tracked the development of cerebellar stem cells in vivo. Under the microscope, they saw the transition of neural stem cells into tumor cells and were able to clearly pinpoint important events. They discovered that a key transcription factor controls the division of neural stem cells by modulating primary cilium. Furthermore, the presence of a defect in primary cilium is able to cause abnormal cerebellar development. This research has become an important milestone in the treatment of brain tumors and their relationship with the loss of primary cilium.

Recently, researchers at NYCU has formed an international research team, including researchers in Australia, United States, and Malaysia, to utilize Next Generation Sequencing to identify new genes associated with “lissencephaly.” Lissencephaly is a serious brain developmental abnormality and patients show serious developmental delay, as well as intractable epilepsy. The most serious patients usually lack language, are unable to swallow and cannot walk; these patients become a huge burden on their families. Lissencephaly is a relatively rare disease and has an incidence of about 12 individuals per million. In Taiwan, there are around 300 cases. The team deintified that loss of function of a novel gene called CEP85L leads to a defect in neural cell migration and this defect is related to the functioning of centrosome. This is the first centrosome composition gene found to be involved in lissencephaly.

A normal brain has many folds called gyri, and these are directly involved in high-order cognitive function development. Patients with lissencephaly have gyri that are underdeveloped or not developed at all; thus their brains have a smooth appearance that is called lissencephaly. The team leader, Distinguished Professor Jin-Wu Tsai of Institute of Brain Science, remarked that part of the lissencephaly phenotype of patients is caused by a genetic mutation. During the development of the brain, neural cells move to the surface of the brain (the cortex) and this process is regulated by many genes. If any of these genes are defective, the neural cells are unable to move to their correct location and this can lead to abnormal development of gyri or lissencephaly. Up to this point, CEP85L had never been associated with any human diseases and thus the identification of mutants of CEP85L and its association with lissencephaly is a world first.

These important discoveries should help to accelerate the diagnosis of different types of abnormal brain developmental diseases by doctors and it also helps to explain why some newborns are found to have this serious disease without any family history. These genes could be used for prenatal screening in the future, which should decrease the occurrence of related. In terms of the science, this research has provided scientists with a deeper understanding of the mechanisms behind brain development and may also help to guide drug development and/or genetic therapy in the future.