In mammalian embryonic gonads, SOX9 is required for the determination of Sertoli cells that orchestrate testis morphogenesis. To identify genetic networks directly regulated by SOX9, we combined analysis of SOX9-bound chromatin regions from murine and bovine foetal testes with sequencing of RNA samples from mouse testes lacking Sox9. We found that SOX9 controls a conserved genetic programme that involves most of the sex-determining genes. In foetal testes, SOX9 modulates both transcription and directly or indirectly sex-specific differential splicing of its target genes through binding to genomic regions with sequence motifs that are conserved among mammals and that we called ‘Sertoli Cell Signature’ (SCS). The SCS is characterized by a precise organization of binding motifs for the Sertoli cell reprogramming factors SOX9, GATA4 and DMRT1. As SOX9 biological role in mammalian gonads is to determine Sertoli cells, we correlated this genomic signature with the presence of SOX9 on chromatin in foetal testes, therefore equating this signature to a genomic bar code of the fate of foetal Sertoli cells. Starting from the hypothesis that nuclear factors that bind to genomic regions with SCS could functionally interact with SOX9, we identified TRIM28 as a new SOX9 partner in foetal testes.

Aims/hypothesis In patients with type 2 diabetes, reduced levels of circulating endothelial progenitor cells have been reported and these have been correlated with disease severity. In this study, we examined a panel of markers widely used to identify progenitor and/or stem cells, and determined their association with disease severity in diabetic patients. Since expression of chemokine (C-X-C motif) receptor 4 (CXCR4) has been associated with mobilisation and recruitment of progenitor cells, CXCR4 expression was also analysed. Methods Peripheral blood mononuclear cells (PBMCs) from 98 patients with type 2 diabetes and 39 control individuals were analysed by flow cytometry for surface marker expression. Results Cells expressing different combinations of progenitor and/or stem cell markers were severely reduced in PBMCs of diabetic patients compared with those of control participants. Moreover, a number of these putative progenitor cell populations were negatively associated with disease severity. Reduced expression of CXCR4 and CD34/CXCR4-positive cells was also observed in diabetic patients. PBMCs expressing CXCR4 positively correlated with levels of progenitor cells in control participants but not in diabetic patients. Levels of putative progenitor and CXCR4-positive cells were further decreased in patients with diabetic complications, including cardiovascular and microvascular diseases. Conclusions/interpretation A generalised decrease in a range of progenitor cell populations was observed in type 2 diabetic patients. This reduction was also negatively associated with disease severity.

Differentiation of germ cells into male gonocytes or female oocytes is a central event in sexual reproduction. Proliferation and differentiation of fetal germ cells depend on the sex of the embryo. In male mouse embryos, germ cell proliferation is regulated by the RNA helicase Mouse Vasa homolog gene and factors synthesized by the somatic Sertoli cells promote gonocyte differentiation. In the female, ovarian differentiation requires activation of the WNT/β-catenin signaling pathway in the somatic cells by the secreted protein RSPO1. Using mouse models, we now show that Rspo1 also activates the WNT/β-catenin signaling pathway in germ cells. In XX Rspo1−/− gonads, germ cell proliferation, expression of the early meiotic marker Stra8, and entry into meiosis are all impaired. In these gonads, impaired entry into meiosis and germ cell sex reversal occur prior to detectable Sertoli cell differentiation, suggesting that β-catenin signaling acts within the germ cells to promote oogonial differentiation and entry into meiosis. Our results demonstrate that RSPO1/β-catenin signaling is involved in meiosis in fetal germ cells and contributes to the cellular decision of germ cells to differentiate into oocyte or sperm.