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Investigation of a mouse model of Prader-Willi Syndrome with combined disruption of Necdin and Magel2
Pierre-Yves Barelle, … , Sebastien G. Bouret, Françoise Muscatelli
Pierre-Yves Barelle, … , Sebastien G. Bouret, Françoise Muscatelli
Published March 6, 2025
Citation Information: JCI Insight. 2025;10(8):e185159. https://doi.org/10.1172/jci.insight.185159.
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Research Article Genetics Neuroscience

Investigation of a mouse model of Prader-Willi Syndrome with combined disruption of Necdin and Magel2

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Abstract

Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of 7 contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. KO mouse models for each candidate gene have been generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay between Necdin and Magel2 PWS genes and generated a mouse model (named Del Ndn-Magel2 mice) with a deletion including both genes. A subset of Del Ndn-Magel2 mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood. Del Ndn-Magel2 mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance as well as altered puberty. Adult mutant 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 similar to patients with PWS. At neuroanatomical levels, Del Ndn-Magel2 mice had an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that the Del Ndn-Magel2 mouse is a pertinent and genetically relevant model of PWS.

Authors

Pierre-Yves Barelle, Alicia Sicardi, Fabienne Schaller, Julie Buron, Denis Becquet, Felix Omnes, Françoise Watrin, Marie-Sophie Alifrangis, Catarina Santos, Clément Menuet, Anne-Marie François-Bellan, Emilie Caron, Jessica Klucznik, Vincent Prevot, Sebastien G. Bouret, Françoise Muscatelli

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Figure 2

Construction and validation of the Del Ndn-Magel2 mouse model.

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Construction and validation of the Del Ndn-Magel2 mouse model.
(A) Strat...
(A) Strategy to obtain a 32 kb deletion including both the Necdin and Magel2 genes using a transallelic recombination approach. First, a female mouse containing 1 maternal allele with the Magel2 deletion, 1 paternal allele with the Necdin deletion, and containing the Hprt-Cre gene was created using both Necdintm1-Mus– and Magel2tm1-Mus–KO models and a transgenic mouse line expressing the Cre recombinase under Hprt promoter. We then crossed these female mice with WT male mice and screened the litter for the recombinant Del Ndn-Magel2 allele using PCR with Necdin sense and Magel2 antisense primers. The Del Ndn-Magel2 allele being created in the ovocytes. (B) PCR product obtained from the recombinant Del Ndn-Magel2 allele (354 bp) in the F1 generation. (C) Sequence of the recombined Del Ndn-Magel2 allele with the Necdin upstream sequence (blue) and Ndn sense primer (bold blue), the LoxP sequence (bold black), and Magel2 sequence (green), and Ml2 anti-sense primer (bold green). This sequence validates the recombination at the loxP sites. (D and E) qPCR analysis showing relative levels of Snord115, Snord116, Mkrn3, Snurf-snron, Magel2, and Necdin mRNAs in the hypothalamus of WT and Del Ndn-Magel2 male (D) and female (E) mice at P60. (F) Images showing Necdin immunoreactivity on sagittal sections of WT and Magel2-KO mouse brains at P7. (G) Breeding strategy to generate Del Ndn-Magel2 and WT litters with an expected ratio of 1 Del Ndn-Magel2/1 WT. (H) Ratio of Del Ndn-Magel2 and WT mice at P21 from 6 cohorts produced in the different laboratories performing experiments for this study. (I) Photos showing cyanosis and lack of milk in the stomach associated to the death of Del Ndn-Magel2 pups at P1. Data are presented as mean ± SEM. Statistical significance between groups was determined by a Mann-Whitney U test (D and E). ***P ≤ 0.002. Scale bar: 400 μm. cer, cerebellum; cx, cortex; hp, hypothalamus; hip, hippocampus.

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