Sexual Development : Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation

The nematode, Caenorhabiditis elegans has proven itself as a valuable model for investigating metazoan biology. Key features including a transparent body, an invariant cell lineage, ease of genetic manipulation, coupled with a high level of genetic conservation with higher eukaryotes make C. elegans a desierable model organism. Although used to elucidate many aspects of somatic biology, a distinct advantage of C. elegans is its well annotated germline which allows all aspects of oogenesis to be observed in real-time within a single animal...

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INTRODUCTION: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls...

BACKGROUND: Encompassing about half of the 60,000 species of vertebrates, fish display the greatest diversity of sex determination mechanisms among metazoans. As such that phylum offers a unique playground to study the impressive variety of gonadal morphogenetic strategies, ranging from gonochorism, with either genetic or environmental sex determination, to unisexuality, with either simultaneous or consecutive hermaphroditism. SUMMARY: From the two main types of gonads, the ovaries embrace the important role to produce the larger and non-motile gametes, which is the basis for the development of a future organism...

INTRODUCTION: The variants in the zinc finger (ZF) domains 1-3 in WT1 are one of the major causes of 46,XY disorders of sex development. Recently, the variants in fourth ZF (ZF4 variants) were reported to cause 46,XX DSD. However, all the nine patients reported were de novo, and no familial cases were identified. CASE PRESENTATION AND RESULTS: The proband (16yrs social female), had 46,XX karyotype with dysplastic testes and moderate virilization in genitalia. A ZF4 variant, p...

Background Primary sex-determination is the developmental process that results in the sex determination of the gonads. Vertebrate sex determination is generally considered to follow the model based on the mammalian system, where a sex-specific master regulatory gene activates one of the two different gene networks that underlie testis and ovary differentiation. Summary It is now known that, while many of the molecular components of these pathways are conserved across different vertebrates, a wide variety of different trigger factors are utilised to initiate primary sex determination...

INTRODUCTION: Cryptorchidism is a hereditary anomaly characterized by the incomplete descent of one or both testicles to the scrotum. One of the challenges of this anomaly is that the retained testicle maintains its endocrine function. As a consequence, cryptorchid animals produce hormone-tainted meat in comparison to castrated animals and are likely to be more aggressive. Cryptorchidism can lead to reduced animal welfare outcomes and cause economic losses. Identifying genetic markers for cryptorchidism is an essential step toward mitigating these negative outcomes and may facilitate genome manipulation to reduce the occurrence of cryptorchidism...

BACKGROUND: A subtype of Disorders of Sex Development (DSD) in individuals with a 46,XX karyotype who are phenotypically male is classified as testicular DSD (46,XX TDSD). These individuals develop testes but are infertile due to germ cell loss. However, little is known about their testicular architecture. METHODS: We analyzed biopsies of four SRY positive 46,XX TDSD men for testicular architecture, Sertoli (SCs) and Leydig cells (LCs). These were compared with biopsies of men with normal spermatogenesis (NS, n=4), men with Klinefelter syndrome, 47 XXY, (KS, n=4), and men with AZF deletion (AZF, n=5)...

INTRODUCTION: Steroid 5-alpha reductase deficiency (5α-R2D) is a rare condition caused by genetic variants that reduce the activity of the enzyme that converts testosterone into dihydrotestosterone. The clinical spectrum of 5α-R2D is known to overlap with other 46,XY differences of sex development (DSD) such as androgen insensitivity or gonadal dysgenesis. However, the clinical trajectories of the aetiologies can differ, with 5α-R2D presenting its own challenges. METHODS: In this study, we have collated clinical information for five individuals with variants in SRD5A2 identified using research genetic testing in an Australian paediatric setting...

Background DNA methylation (DNAme) and histone post-translational 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...

INTRODUCTION: Disorders of sex development (DSDs) are congenital abnormalities in which chromosomal, gonadal, and anatomical sex development are atypical. One of these disorders, 46, XY DSD, is particularly difficult to diagnose and manage because its etiology and clinical phenotypes are highly heterogeneous. METHODS: We used a gene panel containing 141 genes implicated in DSDs to perform targeted next-generation sequencing (NGS) in 50 patients with 46, XY DSD. RESULTS: Gene variants were detected in 23 patients (46%)...

INTRODUCTION: Ovotesticular disorder of sex development (OT-DSD) is a rare condition defined by concomitance of testicular tissue and ovarian tissue (containing follicles) in the same individual. In SRY-negative 46,XX OT-DSD, the presence of testicular tissue may be due to variations in NR5A1. Our aims were to search for NR5A1 variants in SRY-negative 46,XX OT-DSD patients and to perform a systematic review on the contribution of NR5A1 variations to 46,XX OT-DSD. METHODS: Sanger sequencing of NR5A1 was performed in seven SRY-negative 46,XX OT-DSD patients: five simplex cases and two with another sibling with a 46,XX DSD...

CONTEXT: 17α-hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol synthesis, as well as an increased mineralocorticoid effect. AIM: This study aimed to evaluate the clinical, biochemical, and molecular characteristics of patients with 17OHD and to discuss the diagnosis, treatment, and follow-up process. METHODS: Age, symptoms, anthropometric measurements, blood pressure, and hormonal, biochemical, and chromosomal analysis results of 13 patients diagnosed with 17OHD between 2003 and 2022 were recorded at admission and during follow-up...

BACKGROUND: Primordial germ cell (PGC) fate is dictated by the designation, taxis, and influence of the surrounding embryonic somatic cells. Whereas gonadal sex determination results from a balance of factors within the tissue microenvironment. SUMMARY: Our understanding of mammalian ovary development is formed in large part from developmental time courses established using murine models. Genomic tools where genes implicated in the PGC designation or gonadal sex determination have been modulated through complete or conditional knockouts in vivo, and studies in in situ models with inhibitors or cultures that alter the native gonadal environment have pieced together the interplay of pioneering transcription factors, co-regulators and chromosomes critical for the progression of PGCs to oocytes...

BACKGROUND: Persistent müllerian duct syndrome (PMDS) is characterized by the persistence of müllerian duct derivatives in otherwise normally virilized 46,XY males. Biallelic mutations of the anti-müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes lead to PMDS type 1 and 2, respectively. AIM: The aims of the study were to report the clinical, hormonal, and genetic findings in a patient with PMDS and discuss surgical strategies to achieve successful orchidopexy...

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...

BACKGROUND: Reptiles and amphibians provide untapped potential for discovering how a diversity of genetic pathways and environmental conditions are incorporated into developmental processes that can lead to similar functional outcomes. These groups display a multitude of reproductive strategies, and whereas many attributes are conserved within groups and even across vertebrates, several aspects of sexual development show considerable variation. SUMMARY: In this review, we focus our attention on the development of the reptilian and amphibian ovary...

BACKGROUND: Oocytes are a finite and non-renewable resource that are maintained in primordial follicle structures. The ovarian reserve is the totality of primordial follicles, present from birth, within the ovary and its establishment, size, and maintenance dictates the duration of the female reproductive lifespan. Understanding the cellular and molecular dynamics relevant to the establishment and maintenance of the reserve provides the first steps necessary for modulating both individual human and animal reproductive health as well as population dynamics...

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Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear...