Many advances in recent years have added to our understanding of the genetic causes of PWS, including recognition of it as a disorder of genomic imprinting involving defective genes that normally only function after inheritance from the father. At least a dozen genes appear to contribute to the many clinical problems seen in PWS. Unfortunately the exact reasons for development of many of these clinical problems remain elusive. Key among these symptoms are hypoglycemia (low blood sugar) with poor growth and difficulty gaining weight early in life, followed by later excess appetite and life threatening obesity. Using a mouse model of early PWS, we have recently shown that some of the imprinted genes in the critical PWS region affect the production of hormones from specialized cells that are critical for normal growth and body weight, and blood and tissue glucose control. The proposed project will examine these genes to determine how they exert control over production of these hormones and how this is disrupted in PWS. I hypothesize that their abnormal function affects the metabolic balance in the body and directly leads to problems in glucose and weight regulation. A better understanding of these processes will allow the development of new targets for therapy for patients with PWS.