Developmental, behavioral, and metabolic characterization of the Necdin/Magel2 double knockout mouse

Funding Summary

PWS is not the result of a single gene mutation but rather is caused by the loss of several contiguous genes, some of which interact with each other. In this project, Drs. Bouret and Muscatelli will study a new mouse model that lacks two PWS genes, Magel2 and Necdin. The goal is to understand how Magel2 and Necdin act together to influence brain development and behavior. This project is expected to generate an improved understanding of how the brain and behavioral systems are altered in individuals with PWS and may also provide a more relevant mouse model for testing new drugs for PWS.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Please find the full webinar for all funded grants of this cycle here. 

Lay Abstract

The phenotype of patients with Prader-Willi syndrome (PWS) is complex and includes various phases ranging from difficulties feeding at birth to insatiable appetite and behavioral problems during childhood and adulthood. Despite numerous ongoing clinical trials, there is currently no effective treatment for PWS. There is, therefore, an important need to better understand how this syndrome develops in the most appropriate models and use them in “bench to bedside” studies. Pre-clinical animal models have proven to be useful to understand how PWS-related genes impact the brain and behavior. However, most of this research has focused on individual genes, such as Magel2 or Necdin alone. However, PWS is not the result of a single gene mutation but is a complex and multigenic disorder caused by the loss of seven contiguous paternally expressed genes. In addition, many of these genes interact with each other to induce their effects on the body. In this application, we propose to study a new mouse model lacking two genes that also loss in patients with PWS and regulate each other: Magel2 and Necdin. The goal is to understand how Magel2 and Necdin act together to influence brain development and behavior. This project will provide a more relevant understanding of how the brain and behavioral systems are altered in patients with PWS and help develop pre-clinical trials.

Research Outcomes: Public Summary

In this study, we revealed an interplay between Necdin and Magel2 “PWS” genes and characterized the phenotype of a novel mouse model (named “Madin”) with a deletion including both genes. We conducted an extensive phenotypical study of this mouse model, beyond the specific aims proposed in the initial project. An article has been submitted for publication. We showed that a subset of Madin KO mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood. Madin KO 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. Adult Madin KO 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 the Madin KO mouse is a reliable and more genetically relevant model for the study of PWS.

Research Outcomes: Publication

Investigation of a Novel Mouse Model of Prader-Willi Syndrome with Invalidation of Necdin and Magel2. Barelle P-V, Sicardi A, Schaller F, Buron J, Becquet D, Omnes F, Watrin F, Santos C,  Menuet C, François-Bellan A-M, Emilie Caron E, Klucznik J, Prevot V, Bouret SG, Muscatelli F.  biorXiv (2024). doi: 10.1101/2024.07.24.604909.