Sexual Development最新文献

Introduction: Hermaphroditism is a mode of reproduction involving an individual animal that possesses both a testis and an ovary either sequentially or simultaneously. The mechanism creating hermaphrodites remains unknown. Previously, we identified foxl3 as the germline sex determination gene in a gonochoristic fish, medaka (Oryzias latipes). foxl3 loss-of-function (foxl3-/-) females produce functional sperm as well as eggs in the ovary. However, these two gametes are not self-fertilizing because of the histological separation of each gamete production. In this study, we attempted to generate self-fertilizing medaka from female medaka by modifying germline sex using foxl3-/- mutants and by using exogenous androgen to induce partial sex reversal of somatic cells.

Methods: foxl3-/- XX females were treated with 11-ketotestosterone (11-KT), a potent teleost fish androgen, at the sexually mature stage for 30 days (90-120 dph). Then, the fish were kept under normal conditions until they were either being dissected or crossed with infertile males.

Results and discussion: We showed that the foxl3-/- XX female medaka can be transformed into a self-fertilizing hermaphrodite by inducing the formation of a male-like structure with exogenous 11-KT. Self-fertilization occurs in either the ovarian cavity, the oviduct, or both where sperm is released from a tubule-like structure which is likely derived from germinal epithelium, suggesting that timely modification of 2 independent mechanisms, regulation of germline sex and partial sex reversal of somatic cells, are critical to change the reproduction mode. Our results will provide insights in developmental and evolutional occurrence of hermaphrodite vertebrates, facilitate an innovative technique to improve the efficient selection of fish with desirable traits, and contribute to the rescue of endangered species.

Background: Germ cells are critical for the survival of our species. They are the only cells that undergo meiosis - the reductive form of cell division that is necessary for genetic reassortment of chromosomes and production of the haploid gametes, the sperm and eggs. Remarkably, the initial female/male fate decision in fetal germ cells does not depend on whether they are chromosomally XX or XY; rather, initial sexual fate is imposed by influences from the surrounding tissue. In mammals, the female germline is particularly precious: despite recent suggestions that germline stem cells exist in the ovary, it is still generally accepted that the ovarian reserve is finite, and its size is dependant on germ cells of the fetal ovary initiating meiosis in a timely manner.

Summary: Prior to 2006, evidence suggested that gonadal germ cells initiate meiotic prophase I by default, but more recent data support a key role for the signalling molecule retinoic acid (RA) in instructing female germ cell fate. Newer findings also support a key meiosis-inducing role for another signalling molecule, bone morphogenic protein (BMP). Nonetheless, many questions remain.

Key messages: Here, we review knowledge thus far regarding extrinsic and intrinsic determinants of a female germ cell fate, focusing on the mouse model.

Background: DNA methylation (DNAme) and histone posttranslational modifications (PTMs) play an integral role in the transcriptional regulation of specific sets of genes and retrotransposons. In turn, these chromatin marks are essential for cellular reprogramming, including during germline development. While DNAme is stably propagated in most somatic tissues, this epigenetic mark undergoes cycles of widespread erasure and re-establishment in the early embryo as well as in the germline.

Summary: De novo DNAme occurs at distinct developmental stages in male and female germ cells; before birth in prospermatogonia (PSG) and after birth in growing oocytes. Furthermore, while only ∼40% of the mouse genome is methylated in mature oocytes, ∼80% of the genome is methylated in mature sperm. Here, we review recent epigenome studies which reveal a complex interplay between histone PTMs and de novo DNAme in shaping the sexually dimorphic profiles of DNAme observed in mature gametes in the mouse, including in intergenic regions as well as at imprinted gametic differentially methylated regions (gDMRs). We discuss the dynamics and distribution of key histone PTMs in male and female germ cells, including H3K36me2/me3, H3K4me3, and H3K27me3, and the implications of positive and negative crosstalk between these PTMs and the DNAme machinery. Finally, we reflect on how the sex-specific epigenetic landscapes observed in the mouse germline impact transcriptional regulation in both the gametes and the early embryo.

Key messages: Investigation of the roles of chromatin modifying enzymes and the interplay between the chromatin marks that they deposit in germ cells has been facilitated by analyses of conventional or germline-specific knockout mice, combined with low-input genome-wide profiling methods that have been developed in recent years. While clearly informative, these findings generally reflect "snapshots" of chromatin states derived from analyses of cells analyzed in bulk at a specific period in development. Technological advances and novel experimental models will be required to further refine our understanding of the underlying mechanism and order of establishment of chromatin marks and the impact of sexually dimorphic epigenetic patterning on transcription and other nuclear processes in germ cells, the early embryo and beyond.

Background: The establishment of male or female identity (sex determination) is essential for creating the anatomical, physiological, and behavioral differences between 2 sexes of the same species (sexual dimorphism). In many organisms, including mammals and Drosophila, sex is determined by inheritance of sex chromosomes, while in other animals, sex is determined by environmental factors. Arguably the most important consequence of sex determination is the production of healthy gametes necessary for reproduction: female oocytes and male spermatids.

Summary: The generation of sperm and oocytes requires cooperation between 2 different cell types within the gonad: germ cells and somatic cells. Defects in sex determination in either the somatic gonad or germline lead to disorders of sexual development and infertility. In Drosophila, the gene Sex lethal (Sxl) is the key determinant of sex in both the soma and the germline. However, how Sxl controls sex determination is much more well understood in the soma than the germline. Key Mesage: This review will focus on Sxl in the germline, how it is activated specifically in female germ cells, and how it regulates germline sex determination and sexual development.

Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing NR0B1/DAX1 and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the NR0B1/DAX1 gene, may have been the main cause of dysgenetic testes development, although the role of MAGEB and other genes mapped to the Xp21 segment could not be completely ruled out.

Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.