The size of the mammalian body is determined by genetic and environmental factors differentially modulating pre-and postnatal growth. We now report a control of growth acting in the mouse from the first cleavages to the postnatal stages. It was evidenced by a hereditary epigenetic modification (paramutation) created by injection of a miR-124 microRNA into fertilized eggs. From the blastocyst to the adult, mouse pups born after microinjection of this miRNA showed a 30% increase in size. At the blastocyst stage, frequent duplication of the inner cell mass resulted in twin pregnancies. A role of sperm RNA as a transgenerational signal was confirmed by the giant phenotype of the progeny of transgenic males expressing miR-124 during spermiogenesis. In E2.5 to E8.5 embryos, increased levels of several transcripts with sequence homology to the microRNA were noted, including those of Sox9, a gene known for its crucial role in the progenitors of several adult tissues. A role in embryonic growth was confirmed by the large size of embryos expressing a Sox9 DNA transgene. Increased expression in the paramutants was not related to a change in miR-124 expression, but to the establishment of a distinct, heritable chromatin structure in the promoter region of Sox9. While the heritability of body size is not readily accounted for by Mendelian genetics, our results suggest the alternate model of RNAmediated heritable epigenetic modifications.

Transcription controls active at the initial stages of meiosis are clearly key elements in the regulation of germinal differentiation. Transcription of the Sycp1 gene (synaptonemal complex protein 1) starts as early as the leptotene and zygotene stages. Constructs with Sycp1 5' upstream sequences directed the expression of reporter genes to pachytene spermatocytes in transgenic mice. A short fragment encompassing the transcription start (n.t. -54 to +102) was sufficient for stage-specific expression in the adult male and for temporal regulation during development. Upstream enhancer element(s) quantitatively regulating expression were localized in the region between -54 and -260. The gene is normally expressed both in the male and female gonads, but none of the promoter sequences active in the testis allowed the expression of reporter genes during meiosis in the ovary.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which function as transcription factors. Among them, PPARβ/δ is highly expressed in endothelial cells. Pharmacological activation with PPARβ/δ agonists had been shown to increase their angiogenic properties. PPARβ/δ has been suggested to be involved in the regulation of the angiogenic switch in tumor progression. However, until now, it is not clear to what extent the expression of PPARβ/δ in tumor endothelium influences tumor progression and metastasis formation. We addressed this question using transgenic mice with an inducible conditional vascular-specific overexpression of PPARβ/δ. Following specific over-expression of PPARβ/δ in endothelial cells, we induced syngenic tumors. We observed an enhanced tumor growth, a higher vessel density, and enhanced metastasis formation in the tumors of animals with vessel-specific overexpression of PPARβ/δ. In order to identify molecular downstream targets of PPARβ/δ in the tumor endothelium, we sorted endothelial cells from the tumors and performed RNA sequencing. We identified platelet-derived growth factor receptor beta (Pdgfrb), platelet-derived growth factor subunit B (Pdgfb), and the tyrosinkinase KIT (c-Kit) as new PPARβ/δ -dependent molecules. We show here that PPARβ/δ activation, regardless of its action on different cancer cell types, leads to a higher tumor vascularization which favors tumor growth and metastasis formation.

We report the synthesis by mouse testicular cells of antibiotic peptides related to the defensins secreted by the Paneth cells of the intestinal epithelium. A Sertoli cell-derived line (15P-1), Sertoli cells in primary cultures, and explanted testicular tissue in culture medium were observed to release protease-sensitive material with a broad-spectrum antibacterial activity. The activity of 15P-1 culture medium was increased 10- to 50-fold in the presence of fractions enriched in round spermatids and of nerve growth factor. Two series of results suggest that this activity may correspond to the release by testicular cells of defensin peptides, and specifically, of peptides of the cryptdin family first identified in the Paneth cells of intestinal crypts. First, a characteristic nucleotide sequence corresponding to the conserved first exon of the mouse cryptdin and cryptdin-related (CRS) genes was evidenced in the RNA of 15P-1 cells and of the testis. Second, immunohistochemical analysis demonstrated the presence of cryptdins of the cryp-1, -2, -3, -6 group in 15P-1 cells, and identified two distinct localizations in the testis. Inside the seminiferous tubule, these cryptdins were found accumulated in Sertoli cells at stages corresponding to the maturation of spermatids. In the interstitial space, Leydig cells also contained immunoreactive cryptdins.

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Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal western diet feeding for five consecutive generations in mice induces an enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational western-diet-fed males develop a 'healthy' overweight phenotype characterized by normal glucose metabolism and without fatty liver that persists for 4 subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.

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