NF1 Is an Effector and Regulator of the GPCR Signaling in the Nervous System

Neurofibromatosis type 1 NF1 is a monogenic dominant disorder caused by the mutations in the NF1 protein. In addition to developing tumors, NF1 patients suffer from prominent neuropsychiatric symptoms that include cognitive impairments, motor coordination problems, attention difficulties and pain. The focus of this proposal is on molecular mechanisms by which NF1 protein affects signal transduction in the key neuronal pathways and, as such, underlies development of neuropsychiatric problems. During the initial funding period we have achieved significant progress in many of the proposed directions and are on track to continue successful implementation of proposed studies during the next period. Specifically, we have generated all necessary animal models, tools and reagents and applied them to investigate impact of NF1 on 1 cAMP signaling in brain tissues and cultured cells, and 2 Ras signaling in neurons, revealing its key role in transducing signals from opioid receptors. These findings will likely have an impact on understanding signaling disruptions in neurofibromatosis and development of innovative therapeutic strategies.