Investigation of a Novel Mouse Model of Prader-Willi Syndrome with Invalidation ofNecdinandMagel2

Abstract

AbstractPrader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene were generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay betweenNecdinandMagel2“PWS” genes and generated a novel mouse model (named “Madin”) with a deletion including both genes. A subset ofMadinKO mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood.MadinKO mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance. Delayed sexual maturation and altered timing of puberty onset were observed in mutant mice. AdultMadinKO mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function that were also found in the hypothalamus of patients with PWS. At neuroanatomical levels, we report an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that theMadinKO mouse is a reliable and more genetically relevant model for the study of PWS.