CCR4-Associated Factor CAF1 Is an Essential Factor for Spermatogenesis

The CCR4-associated protein CAF1 has been demonstrated to play several roles in the control of transcription and of mRNA decay. To gain further insight into its physiological function, we generated CAF1-deficient mice. They are viable, healthy, and normal in appearance; however, mCAF1(−/−) male mice are sterile. The crossing of mCAF1(+/−) mice gave a Mendelian ratio of mCAF1(+/+), mCAF1(+/−), and mCAF1(−/−) pups, indicating that haploid mCAF1-deficient germ cells differentiate normally. The onset of the defect occurs during the first wave of spermatogenesis at 19 to 20 days after birth, during progression of pachytene spermatocytes to haploid spermatids and spermatozoa. Early disruption of spermatogenesis was evidenced by Sertoli cell vacuolization and tubular disorganization. The most mature germ cells were the most severely depleted, but progressively all germ cells were affected, giving Sertoli cell-only tubes, large interstitial spaces, and small testes. This phenotype could be linked to a defect(s) in germ cells and/or to inadequate Sertoli cell function, leading to seminiferous tubule disorganization and finally to a total disappearance of germ cells. The mCAF1-deficient mouse provides a new model of failed spermatogenesis in the adult that may be relevant to some cases of human male sterility

Deregulation of anti-Mullerian hormone/BMP and transforming growth factor-{beta} pathways in Leydig cell lesions developed in male heterozygous multiple endocrine Neoplasia type 1 mutant mice

International audienceMultiple 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-beta (TGF-beta) 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-beta pathways, is altered in the Leydig cell lesions. Our data provide the evidence of the deregulation of AMH/BMP and TGF-beta pathways in mouse Men1 LCTs, highlighting their involvement in tumorigenesis of Leydig cells due to Men1 inactivation

Aménagement et environnement

Fréquemment assimilé aux politiques publiques qui ont accompagné la reconstruction postérieure à la Seconde Guerre mondiale, l'aménagement du territoire tel qu'on le concevait alors visait la modernisation du pays. Il était pensé comme facteur de progrès a priori et reposait sur une conception techniciste qui voyait dans des ingénieurs les seules autorités compétentes, excluant l'expérience des populations. Les nuisances et les bouleversements de tous ordres induits par les aménagements étaient considérés comme négligeables, le prix à payer dans l'intérêt général. Leur contestation ne pouvait être motivée que par l'ignorance ou l'égoïsme. Les dix-neuf contributions réunies dans ce livre proposent une vision nouvelle des aménagements territoriaux. Pensant les territoires comme des champs de négociation où s'affrontent des forces variées, elles cherchent à inclure dans l'étude de leur aménagement la façon dont l'environnement, que les sociétés cherchent à maîtriser et à mettre au service de leurs desseins, réagit à son tour à la transformation imposée. Considérant des aménagements effectués à toutes les périodes de l'histoire, elles cherchent à identifier leur impact économique, social, environnemental ou même culturel, y compris sur le long terme. Une tentative ambitieuse, tant il est vrai que même lorsque les aménagements passés sont identifiés comme des échecs, voire comme des réalisations néfastes, par leurs auteurs eux-mêmes, il est bien rare que cela soit exprimé publiquement