Smith-Magenis syndrome (SMS) is an autism-like neurodevelopmental disorder that causes, among other things, motor and learning disability and obesity. SMS affects 1 in 15,000 to 25,000 people, mostly due to the spontaneous loss of a segment of chromosome 17 in the sperm or the egg that produces the embryo. Loss of one copy of the RAI1 gene, which is located within this chromosomal region, recapitulates most of the symptoms of SMS. Further, having an extra copy of the RAI1-containing segment causes the autism spectrum disorder Potocki-Lupski syndrome (PTLS). While alterations in RAI1 copy number has been linked to a number of neurodevelopmental disorders, the precise function of RAI1 in the brain remains unclear. Liqun Luo and his colleagues at Stanford University aim to understand why changing RAI1 copy number leads to compromised cognitive ability and autism-like symptoms.
The RAI1 gene in mice is highly similar to human RAI1. Losing one copy of the RAI1 gene in mice causes minimal effects, whereas losing both copies causes most mice to die in utero and before the nervous system has a chance to develop. Supported by a SFARI Pilot Award, Luo’s team previously produced mice that lack both copies of RAI1 in specified cell populations. Whole-brain-specific removal of both RAI1 copies produces viable mice that reach adulthood but die young, exhibit obesity and have both motor and learning defects. These obesity and motor and learning defects mimic phenotypes seen in humans with SMS.
In the current study, the researchers propose to refine their mapping efforts to pinpoint more precisely the key neural cell types in which RAI1 functions to regulate normal weight control and learning. They will also determine whether RAI1 function in these cell types is needed during brain development, in adulthood, or both. Finally, their current data suggest that RAI1’s primary function is to regulate the expression of other genes. Luo and his team will use modern genetic and genomic techniques to identify RAI1 target genes and investigate how RAI1 regulates the expression of these genes.