Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies.

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. SOX8 is an HMG-box transcription factor closely related to SRY and SOX9. Deletion of the gene encoding Sox8 in mice causes reproductive dysfunction but the role of SOX8 in humans is unknown. Here, we show that SOX8 is expressed in the somatic cells of the early developing gonad in the human and influences human sex determination. We identified two individuals with 46, XY disorders/differences in sex development (DSD) and chromosomal rearrangements encompassing the SOX8 locus and a third individual with 46, XY DSD and a missense mutation in the HMG-box of SOX8. In vitro functional assays indicate that this mutation alters the biological activity of the protein. As an emerging body of evidence suggests that DSDs and infertility can have common etiologies, we also analysed SOX8 in a cohort of infertile men (n=274) and two independent cohorts of women with primary ovarian insufficiency (POI; n=153 and n=104). SOX8 mutations were found at increased frequency in oligozoospermic men (3.5%; P < 0.05) and POI (5.06%; P=4.5×10 -5 ) as compared with fertile/normospermic control populations (0.74%). The mutant proteins identified altered SOX8 biological activity as compared with the wild-type protein. These data demonstrate that SOX8 plays an important role in human reproduction and SOX8 mutations contribute to a spectrum of phenotypes including 46, XY DSD, male infertility and 46, XX POI.Link_to_subscribed_fulltex

Transcriptional control of kidney development by the Sox genes family

Les anomalies congénitales du rein et du tractus urinaire (CAKUT) sont l’une des malformations les plus fréquentes chez l’homme, et résultent d’un défaut du programme de dévelopement des organes. La famille de gènes Sox code pour 20 facteurs de transcription qui assurent des fonctions multiples et essentielles pendant l’organogenèse chez l’homme et la souris. Nous avons précedemment montré que Sox8 et Sox9 sont nécessaires au branchement de l’uretère, et la perte de ces gènes résulte en une agénésie rénale. L’objectif de ce projet de thèse était de caractériser le role des gènes Sox-C (Sox4/11/12) in vivo chez la souris. L’analyse des patrons d’expression a révélé que Sox4 , Sox11 et Sox12 sont co-exprimés dans les cellules progénitirices des néphrons, destinées à subir une transition mésenchyme epithelium (MET) pour former des vésicules qui s'allongent pour aboutir au néphron fonctionnel. L’analyse phénotypique a révélé une redondance fonctionnelle entre Sox4 et Sox11 pendant les processus de MET et de maturation des néphrons: les double mutants développent une hypodysplasie rénale dûe à une réduction dramatique du nombre et de la taille des néphrons. Le pool de progéniteurs de néphrons est intact chez ces mutants mais incapable de s’engager dans la nephrogenèse, probablement dû à un changement d’identité cellulaire. Par ailleurs, en l’absence de Sox11, des bourgeons uretéraux ectopiques se forment, conduisant à des reins duplex, phénotype présent dans une proportion de patients CAKUT. De manière importante, nous avons identifié une série de variants SOX11 dans une cohorte de patients CAKUT, suggérant l'implication de mutations SOX11 dans cette maladie chez l'homme.Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the mostcommon birth defects in human and are caused by defects in the program governing organ development. The Sox gene family encodes 20 transcription factors that ensure multiple and essential functions during mouse and human organogenesis. We have previously shown that the homologous genes Sox8 and Sox9 are required for the branching process of the ureter and their loss results in renal agenesis. In this thesis project, we aimed to identify and characterize the role of the Sox-C genes (Sox4/11/12), in vivo using mouse models. Expression analysis revealed that Sox4, Sox11 and Sox12 are coexpressed in the self-renewing nephron precursors cells that are destined to undergo mesenchyme-to-eptihelial transition (MET) to form vesicles that elongate to give rise to the functional nephrons. Phenotypical analysis revealed a functional redundancy between Sox4 and Sox11 in MET and nephron maturation processes: double mutants display renal hypodysplasia, due to a dramatic reduction in the number and size of nephrons. The nephron precursor pool is intact in these mutants but unable to commit to nephrogenesis, probably because of a cell identity change. In addition, in the absence of Sox11, ectopic ureteric buds form, leading to duplex kidneys, a phenotype found in a proportion of CAKUT patients. Importantly, mutation analysis of a cohort suffering from CAKUT syndrome identified a series of SOX11 variants, thus suggesting an involvement of SOX11 mutations in this human disease

The Insulin/IGF System in Mammalian Sexual Development and Reproduction

Persistent research over the past few decades has clearly established that the insulin-like family of growth factors, which is composed of insulin and insulin-like growth factors 1 (IGF1) and 2 (IGF2), plays essential roles in sexual development and reproduction of both males and females. Within the male and female reproductive organs, ligands of the family act in an autocrine/paracrine manner, in order to guide different aspects of gonadogenesis, sex determination, sex-specific development or reproductive performance. Although our knowledge has greatly improved over the last years, there are still several facets that remain to be deciphered. In this review, we first briefly outline the principles of sexual development and insulin/IGF signaling, and then present our current knowledge, both in rodents and humans, about the involvement of insulin/IGFs in sexual development and reproductive functions. We conclude by highlighting some interesting remarks and delineating certain unanswered questions that need to be addressed in future studies

Transcriptional control of kidney development by the Sox genes family

Les anomalies congénitales du rein et du tractus urinaire (CAKUT) sont l une des malformations les plus fréquentes chez l homme, et résultent d un défaut du programme de dévelopement des organes. La famille de gènes Sox code pour 20 facteurs de transcription qui assurent des fonctions multiples et essentielles pendant l organogenèse chez l homme et la souris. Nous avons précedemment montré que Sox8 et Sox9 sont nécessaires au branchement de l uretère, et la perte de ces gènes résulte en une agénésie rénale. L objectif de ce projet de thèse était de caractériser le role des gènes Sox-C (Sox4/11/12) in vivo chez la souris. L analyse des patrons d expression a révélé que Sox4 , Sox11 et Sox12 sont co-exprimés dans les cellules progénitirices des néphrons, destinées à subir une transition mésenchyme epithelium (MET) pour former des vésicules qui s'allongent pour aboutir au néphron fonctionnel. L analyse phénotypique a révélé une redondance fonctionnelle entre Sox4 et Sox11 pendant les processus de MET et de maturation des néphrons: les double mutants développent une hypodysplasie rénale dûe à une réduction dramatique du nombre et de la taille des néphrons. Le pool de progéniteurs de néphrons est intact chez ces mutants mais incapable de s engager dans la nephrogenèse, probablement dû à un changement d identité cellulaire. Par ailleurs, en l absence de Sox11, des bourgeons uretéraux ectopiques se forment, conduisant à des reins duplex, phénotype présent dans une proportion de patients CAKUT. De manière importante, nous avons identifié une série de variants SOX11 dans une cohorte de patients CAKUT, suggérant l'implication de mutations SOX11 dans cette maladie chez l'homme.Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the mostcommon birth defects in human and are caused by defects in the program governing organ development. The Sox gene family encodes 20 transcription factors that ensure multiple and essential functions during mouse and human organogenesis. We have previously shown that the homologous genes Sox8 and Sox9 are required for the branching process of the ureter and their loss results in renal agenesis. In this thesis project, we aimed to identify and characterize the role of the Sox-C genes (Sox4/11/12), in vivo using mouse models. Expression analysis revealed that Sox4, Sox11 and Sox12 are coexpressed in the self-renewing nephron precursors cells that are destined to undergo mesenchyme-to-eptihelial transition (MET) to form vesicles that elongate to give rise to the functional nephrons. Phenotypical analysis revealed a functional redundancy between Sox4 and Sox11 in MET and nephron maturation processes: double mutants display renal hypodysplasia, due to a dramatic reduction in the number and size of nephrons. The nephron precursor pool is intact in these mutants but unable to commit to nephrogenesis, probably because of a cell identity change. In addition, in the absence of Sox11, ectopic ureteric buds form, leading to duplex kidneys, a phenotype found in a proportion of CAKUT patients. Importantly, mutation analysis of a cohort suffering from CAKUT syndrome identified a series of SOX11 variants, thus suggesting an involvement of SOX11 mutations in this human disease.NICE-Bibliotheque electronique (060889901) / SudocSudocFranceF

The insulin/IGF system in mammalian sexual development and reproduction

Persistent research over the past few decades has clearly established that the insulin-like family of growth factors, which is composed of insulin and insulin-like growth factors 1 (IGF1) and 2 (IGF2), plays essential roles in sexual development and reproduction of both males and females. Within the male and female reproductive organs, ligands of the family act in an autocrine/paracrine manner, in order to guide different aspects of gonadogenesis, sex determination, sex-specific development or reproductive performance. Although our knowledge has greatly improved over the last years, there are still several facets that remain to be deciphered. In this review, we first briefly outline the principles of sexual development and insulin/IGF signaling, and then present our current knowledge, both in rodents and humans, about the involvement of insulin/IGFs in sexual development and reproductive functions. We conclude by highlighting some interesting remarks and delineating certain unanswered questions that need to be addressed in future studies

Tumor Suppressor PTEN Regulates Negatively Sertoli Cell Proliferation, Testis Size, and Sperm Production In Vivo

The IGFs are the major intratesticular factors regulating immature Sertoli cell proliferation and are, therefore, critical to establish the magnitude of sperm production. However, the intratesticular source of IGF production and the downstream signaling pathway mediating IGF-dependent Sertoli cell proliferation remain unclear. Single-cell RNA sequencing on mouse embryonic testis revealed a robust expression of Igf1 and Igf2 in interstitial steroidogenic progenitors, suggesting that IGFs exert paracrine actions on immature Sertoli cells. To elucidate the intracellular signaling mechanism that underlies the proliferative effects of IGFs on immature Sertoli cells, we have generated mice with Sertoli cell-specific deletion of the Pten gene, a negative regulator of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway, alone or together with the insulin receptor (Insr) and the IGF1 receptor (Igf1r). Although ablation of Pten appears dispensable for Sertoli cell proliferation and spermatogenesis, inactivation of Pten in the absence of Insr and Igf1r rescued the Sertoli cell proliferation rate during late fetal development, testis size, and sperm production. Overall, these findings suggest that IGFs secreted by interstitial progenitor cells act in a paracrine fashion to promote the proliferation of immature Sertoli cells through the IGF/PTEN/PI3K pathway

Deciphering the origins and fates of steroidogenic lineages in the mouse testis

Leydig cells (LCs) are the major androgen-producing cells in the testis. They arise from steroidogenic progenitors (SPs), whose origins, maintenance, and differentiation dynamics remain largely unknown. Single-cell transcriptomics reveal that the mouse steroidogenic lineage is specified as early as embryonic day 12.5 (E12.5) and has a dual mesonephric and coelomic origin. SPs specifically express the Wnt5a gene and evolve rapidly. At E12.5 and E13.5, they give rise first to an intermediate population of pre-LCs, and finally to fetal LCs. At E16.5, SPs possess the characteristics of the dormant progenitors at the origin of adult LCs and are also transcriptionally closely related to peritubular myoid cells (PMCs). In agreement with our in silico analysis, in vivo lineage tracing indicates that Wnt5a-expressing cells are bona fide progenitors of PMCs as well as fetal and adult LCs, contributing to most of the LCs present in the fetal and adult testis

Sox11 gene disruption causes congenital anomalies of the kidney and urinary tract (CAKUT)

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Specific transcriptomic signatures and dual regulation of steroidogenesis between fetal and adult mouse leydig cells

Leydig cells (LC) are the main testicular androgen-producing cells. In eutherian mammals, two types of LCs emerge successively during testicular development, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs). Both display significant differences in androgen production and regulation. Using bulk RNA sequencing, we compared the transcriptomes of both LC populations to characterize their specific transcriptional and functional features. Despite similar transcriptomic profiles, a quarter of the genes show significant variations in expression between FLCs and ALCs. Non-transcriptional events, such as alternative splicing was also observed, including a high rate of intron retention in FLCs compared to ALCs. The use of single-cell RNA sequencing data also allowed the identification of nine FLC-specific genes and 50 ALC-specific genes. Expression of the corticotropin-releasing hormone 1 (Crhr1) receptor and the ACTH receptor melanocortin type 2 receptor (Mc2r) specifically in FLCs suggests a dual regulation of steroidogenesis. The androstenedione synthesis by FLCs is stimulated by luteinizing hormone (LH), corticotrophin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) whereas the testosterone synthesis by ALCs is dependent exclusively on LH. Overall, our study provides a useful database to explore LC development and functions