The MAGED1 gene is located on the X chromosome, it belongs to the group/category of type II MAGE genes , which are expressed in various tissues during embryonic development and in adult organism. Among the type II MAGE genes, NECDIN and MAGEL2 are probably the most studied because of their putative involvement in the etiology of the Prader-Willi syndrome. Indeed, these two genes are located in the 15q11-q13 region that is absent in most people with the Prader-Willi syndrome. The most striking feature of individuals suffering from Prader-Willi syndrome is their hyperphagic behavior which leads to the development of morbid obesity if their food intake is not controlled. To investigate the function of Maged1 in vivo, Maged1- mice were previously obtained by gene targeting in our laboratory. Curiously, as it is observed in people with the Prader-Willi syndrome, the Maged1- mutants exhibit hyperphagia and develop obesity, although this obesity is milder and appears later compared to what is observed in individuals suffering from Prader-Willi syndrome. Maged1- knockout mice have also behavioral defects similar to those observed in autistic individuals. Interestingly 25% of the people with Prader-Willi syndrome also develop autism. To characterize the autistic-like behaviors of the Maged1- knockout mice, we submitted these mice to a battery of tests. The Maged1- knockout mice exhibited a reduced sociability in the test of reciprocal social interactions. In the three chamber experiment, the Maged1- mutants remained at distance of the mouse stimulus and a concomitant reduction in direct social interactions was observed. Finally in the social memory test, the Maged1- knockout mice were unable to discriminate a new partner from a familiar one. The Maged1- mutants also displayed reduced ultrasonic communications during courtship behavior and a severe reduction of coital activity. Besides defects in social interactions and communications, Maged1- mutants are hypoactive and display anxiety-like behaviors such as exaggerated self-grooming. This association of behavioral defects allows us to propose Maged1- knockout mice as a new model of “autistic mice”. Loss of function of Maged1 gene in mice also leads to a reduced production of mature oxytocin, while the precursor and intermediate forms of this neuropeptide are normally synthesized. The lack of mature oxytocin may explain some of the phenotypes displayed by the knockout mice. Indeed, oxytocin is known to be involved in the regulation of food intake, social behavior, anxiety and sexual behavior. To demonstrate the role of oxytocin in the altered behavior of the Maged1- mice, we showed that peripheral injection of oxytocin rescued the social memory of these animals. Altogether, our results demonstrate an essential role for Maged1 in the regulation of social and sexual behaviors as well as in the control of metabolism which are in part explained by the regulation of mature oxytocin production by Maged1.
La déficience en Maged1 chez la souris entraîne une diminution de la production d’ocytocine par l’hypothalamus, provoque de l’obésité et altère les comportements sociaux et sexuels.
Dombret, C. (Author). 7 Sept 2012
Student thesis: Doc types › Doctor of Biomedical and Pharmaceutical Sciences