The long-term goal of this proposal is to establish successful independent laboratory using mouse models to study the neurobiology and treatment of Smith-Magenis Syndrome (SMS), a devastating neurodevelopmental disorder caused by haploinsufficiency of RAI1. SMS patients exhibit prominent neurologic symptoms, including intellectual disabilities, sleep disturbances, seizures, hypotonia, self-injurious behaviors, and autistic features. We recently discovered that Rai1 is a transcription factor that promotes the expression of several genes important for neuronal morphogenesis and neurotransmission. However, the mechanism by which Rai1 regulates neuronal morphology and activity, thereby causing the neurobehavioral symptoms is unclear. Furthermore, we also lack fundamental understanding about when during development is RAI1 required for neural functions, and whether SMS symptoms are reversible if RAI1 dosage is restored in adults. The objectives of this proposal are to (1) determine critical temporal windows for Rai1 requirement and correct SMS-like phenotypes; (2) determine the role of Rai1 in neuronal morphogenesis; and (3) determine how loss of Rai1 shapes neuronal activity. The central hypothesis is that Rai1 regulates the morphogenesis and circuit activity homeostasis. Restoring Rai1 in critical temporal windows will ameliorate at least some SMS-like phenotypes in mice. This hypothesis will be tested using cutting-edge neuroscience techniques in combination with novel mouse genetic tools. Completion of the proposed experiments will determine the reversibility of various neurobehavioral and physiological phenotypes of SMS, identify the critical treatment window, and elucidate the anatomical and activity level deficits underlying SMS symptoms. These results will serve as the foundation for future studies aimed to reverse these deficits. The mentored phase of this award will be overseen by a team of world renowned neuroscientists including Drs. Liqun Luo, John Huguenard, Mehrdad Shamloo, and John Swann. Upon completion of the mentored phase that focuses on studying the role of Rai1 in neuronal morphology and activity, the PI will be able to link the molecular functions of Rai1 to its behavioral functions. A comprehensive training plan was proposed to include additional education in single cell dendritic morphological analysis and electrophysiological recordings. Completion of this proposal will provide the necessary skills to transition to an independent faculty position at a top research institution.
Smith-Magenis Syndrome is a devastating neurodevelopmental disorder with prominent neurobehavioral features and little treatment options. The neurobiology of the disease-defining gene, RAI1, has remained unclear. The goal of this project is to identify critical therapeutic window for SMS, and elucidate the role of Rai1 in neuronal morphogenesis and circuit homeostasis. This project will uncover potential pathogenic mechanisms, and have a direct impact on the therapeutic design for SMS.