Investigating commissions of the Chamber of Deputies and their influence on political reality

Katedra politologieDepartment of Political ScienceFakulta sociálních vědFaculty of Social Science

Paternal epigenetics: Mammalian sperm provide much more than DNA at fertilization

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Oligogenic heterozygous inheritance of sperm abnormalities in mouse

Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects - the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man

When idiopathic male infertility is rooted in maternal malnutrition during the perinatal period in mice

International audienceAbstract Infertility represents a growing burden worldwide, with one in seven couples presenting difficulties conceiving. Amongst these, 10–15% of the men have idiopathic infertility that does not correlate with any defect in the classical sperm parameters measured. In the present study, we used a mouse model to investigate the effects of maternal undernutrition on fertility in male progeny. Our results indicate that mothers fed on a low protein diet during gestation and lactation produce male offspring with normal sperm morphology, concentration and motility but exhibiting an overall decrease of fertility when they reach adulthood. Particularly, in contrast to control, sperm from these offspring show a remarkable lower capacity to fertilize oocytes when copulation occurs early in the estrus cycle relative to ovulation, due to an altered sperm capacitation. Our data demonstrate for the first time that maternal nutritional stress can have long-term consequences on the reproductive health of male progeny by affecting sperm physiology, especially capacitation, with no observable impact on spermatogenesis and classical quantitative and qualitative sperm parameters. Moreover, our experimental model could be of major interest to study, explain, and ultimately treat certain categories of infertilities

Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse

International audienceGenetic mutations are a recurrent cause of male infertility. Multiple morphological abnormalities of the flagellum (MMAF) syndrome is a heterogeneous genetic disease, with which more than 50 genes have been linked. Nevertheless, for 50% of patients with this condition, no genetic cause is identified. From a study of a cohort of 167 MMAF patients, pathogenic bi-allelic mutations were identified in the CCDC146 gene in two patients. This gene encodes a poorly characterized centrosomal protein which we studied in detail here. First, protein localization was studied in two cell lines. We confirmed the centrosomal localization in somatic cells and showed that the protein also presents multiple microtubule-related localizations during mitotic division, suggesting that it is a microtubule-associated protein (MAP). To better understand the function of the protein at the sperm level, and the molecular pathogenesis of infertility associated with CCDC146 mutations, two genetically modified mouse models were created: a Ccdc146 knockout (KO) and a knock-in (KI) expressing a HA-tagged CCDC146 protein. KO male mice were completely infertile, and sperm exhibited a phenotype identical to our two MMAF patient's phenotype with CCDC146 mutations. No other pathology was observed, and the animals were viable. CCDC146 expression starts during late spermiogenesis, at the time of flagellum biogenesis. In the spermatozoon, the protein is conserved but is not localized to centrioles, unlike in somatic cells, rather it is present in the axoneme at the level of microtubule doublets. Expansion microscopy associated with the use of the detergent sarkosyl to solubilize microtubule doublets, provided evidence that the protein could be a microtubule inner protein (MIP). At the subcellular level, the absence of CCDC146 affected the formation, localization and morphology of all microtubule-based organelles such as the manchette, the head-tail coupling apparatus (HTCA), and the axoneme. Through this study, we have characterized a new genetic cause of infertility, identified a new factor in the formation and/or structure of the sperm axoneme, and demonstrated that the CCDC146 protein plays several cellular roles, depending on the cell type and the stages in the cell cycle

Paternal epigenetics: Mammalian sperm provide much more than DNA at fertilization

International audienceThe spermatozoon is a highly differentiated cell with unique characteristics: it is mobile, thanks to its flagellum, and is very compact. The sperm cytoplasm is extremely reduced, containing no ribosomes, and therefore does not allow translation, and its nucleus contains very closed chromatin, preventing transcription. This DNA compaction is linked to the loss of nucleosomes and the replacement of histones by protamines. Based on these characteristics, sperm was considered to simply deliver paternal DNA to the oocyte. However, some parts of the sperm DNA remain organized in a nucleosomal format, and bear epigenetic information. In addition, the nucleus and the cytoplasm contain a multitude of RNAs of different types, including non-coding RNAs (ncRNAs) which also carry epigenetic information. For a long time, these RNAs were considered residues of spermatogenesis. After briefly describing the mechanisms of compaction of sperm DNA, we focus this review on the origin and function of the different ncRNAs. We present studies demonstrating the importance of these RNAs in embryonic development and transgenerational adaptation to stress. We also look at other epigenetic marks, such as DNA methylation or post-translational modifications of histones, and show that they are sensitive to environmental stress and transmissible to offspring. The post-fertilization role of certain sperm-borne proteins is also discussed