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¹ Université Claude Bernard Lyon, Lyon, France; Faculté de Médecine, Université Lyon 1, Lyon F-69003, France; Laboratoire Génétique Moléculaire, Signalisation et Cancer, 8 Avenue Rockefeller, Lyon F-69373, France² CNRS UMR5201, Lyon F69373, France³ INSERM-INRA U418, Hôpital Debrousse, Lyon F-69322, France⁴ INSERM, U782, Clamart F-92140, France; Univ Paris-Sud, UMR-S0782, Clamart F-92140, France⁵ Groupe d'Etude Recherche, CNRS No 2906, Lyon, France

(Correspondence should be addressed to C X Zhang, Laboratoire Génétique Moléculaire, Signalisation et Cancer, CNRS, UMR5201, Faculté de Médecine, Université Claude Bernard Lyon 1, 8 Avenue Rockefeller, 69373 Lyon, France; Email: zhang{at}sante.univ-lyon1.fr)

Multiple endocrine neoplasia type 1 (MEN1) results from the mutation of the predisposing gene, MEN1. Heterozygous Men1 mutant mice previously generated by several laboratories, including ours, mimic largely MEN1 pathology. Interestingly, our heterozygous Men1 mutant mice exhibit not only the endocrine tumours commonly seen in MEN1 patients, but also Leydig cell tumours (LCT) with high frequency, accompanied systematically by loss of the wild-type Men1 allele. As there exists a similarity of tumour phenotype between these mice and those mutated for the components of anti-Mullerian hormone (AMH)/bone morphogenic protein (BMP) pathway belonging to transforming growth factor-β (TGF-β) family, we investigated the expression and the activity of this pathway, known to have an important biological role in Leydig cells. Here, we report that the expression of AMH receptor type 2 is reduced in Men1 LCTs. Both immunostaining and western blot analyses also demonstrate a markedly decreased nuclear expression of Smad1, 3, 4 and 5 in the tumours. More interestingly, we show that the reconstituted menin expression in Men1-deficient Leydig cells derived from LCTs can significantly increase the transcriptional activity of a BMP pathway target promoter, XVent2. Furthermore, we found that the expression of p18, p27 and cyclin dependant kinase 4 (Cdk4), targets of TGF-β pathways, is altered in the Leydig cell lesions. Our data provide the evidence of the deregulation of AMH/BMP and TGF-β pathways in mouse Men1 LCTs, highlighting their involvement in tumorigenesis of Leydig cells due to Men1 inactivation.