The overall goals of our research are to elucidate the genetic and pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS. We believe that a detailed level of understanding is necessary to design rational interventions. Recently, our laboratory has focused on the role of a special type of RNA, called PWCR1/HBII-85 small nucleolar RNA (snoRNA) that we discovered in 2001. Since then, studies of rare cases of PWS with smaller deletions and chromosome rearrangements allowed us to narrow the minimal critical region from 4 Million DNA building blocks (nucleotides) to only 121,000. It is within this region where the PWCR1/HBII-85snoRNA genes reside. These snoRNAs are completely absent in the brain of PWS individuals, and they are the only known genetic elements in the PWS minimal critical region that are conserved between humans and mice. With previous support of FPWR, we succeeded in creating a mouse model that lacks the expression of the Pwcr1/MBII-85 snoRNA cluster. The pre-existing PWS mouse models with large genomic deletions rarely survive after birth. Our new mouse model shows the same postnatal growth retardation as previous mouse models, but most mice survive the critical newborn period and can now be studied functionally for the development of clinical manifestations throughout life. In the work we propose here, we will carry out a thorough characterization of this new mouse model in terms of growth regulation, appetite control, behavior profile and cognitive functions. Alterations in expression of specific genes will be assessed by global expression microarray studies of different brain regions at different ages. We plan to document clinical endpoints that can then be targeted by therapeutic interventions in future work.