Disruption of the mouse Necdin gene results in hypothalamic and behavioralalterations reminiscent of the human Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with conside rable clinical variability that is thought in large part to be the result o f a hypothalamic defect. PWS results from the absence of paternal expressio n of imprinted genes localized in the 15q11-q13 region; however, none of th e characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficien t for Necdin. Linked to the mutation, a neonatal lethality of variable pene trance is observed. Viable Necdin mutants show a reduction in both oxytocin -producing and luteinizing hormone-releasing hormone (LHRH)producing neuron s in hypothalamus. This represents the first evidence of a hypothalamic def iciency in a mouse model of PWS. Necdin-deficient mice also display increas ed skin scraping activity in the open field test and improved spatial learn ing and memory in the Morris water maze. The latter features are reminiscen t of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, e motional and cognitive-related behaviors strongly suggest that NECDIN is re sponsible for at least a subset of the multiple clinical manifestations of PWS.