Taking an innovative approach to the investigation of genetic syndromes causing learning disabilities and mental retardation, researchers at The Hospital for Sick Children (SickKids) and Harvard Medical School have found that neural stem cell development during embryogenesis may have a direct effect on abnormal brain development. This research is reported in the April 19 issue of Neuron.
Typically studies of this nature focus on problems with how neural circuits function. These neural circuits form the nervous system and without a properly functioning circuit, a host of complications and disorders can arise. Investigating this problem from a different angle, the SickKids team decided to look at how neural circuits are formed, and more importantly, how nerve cells develop during embryogenesis.
“We thought that some of these genetic defects might be related to neural stem cell function, and lead to abnormal development right from the start,” said Dr. Freda Miller, the study’s principal investigator, a senior scientist in Developmental Biology in the SickKids Research Institute, a professor of Molecular and Medical Genetics, and Physiology at the University of Toronto and Canada Research Chair in Developmental Neurobiology.
“We identified a protein that tells stem cells to make neurons during embryogenesis. This protein is implicated in a human genetic syndrome, and we then showed that the mutant form of the protein disturbs this stem cell differentiation into nerve cells, something that has significant bearing on the development of learning disabilities and mental retardation,” Miller added.
Miller and her team focused on the human genetic disorder Noonan syndrome, a disorder where the SHP-2 protein is mutated, causing abnormal development of multiple parts of the body. The team found that mutation of this protein changed how neural stem cells generate the different cells of the embryonic brain; when SHP-2 was altered in a mouse model of Noonan syndrome, early neural development was disturbed.
“This suggests that the human problems likely arise, at least in part from altered neural stem cell function,” adds Miller.
In addition, there is a family of related disorders, including Costello syndrome and Cardio-facio-cutaneous (CFC) syndrome, which show severe mental retardation, and which the research team predicts would have similar problems with neural stem cells. The group is now hoping to ask if similar alterations might underlie the neural problems in these genetic disorders.
Members of the research team were Dr. David Kaplan, Andrée Gauthier and Oliva Furstoss from SickKids, and Toshiyuki Araki, Richard Chan and Benjamin Neel from Harvard Medical School.