Sexual Development最新文献

Disorders of sex development (DSD) are a complex group of conditions with highly variable clinical phenotypes, most often caused by failure of gonadal development. DSD are estimated to occur in around 1.7% of all live births. Whilst the understanding of genes involved in gonad development has increased exponentially, approximately 50% of patients with a DSD remain without a genetic diagnosis, possibly implicating non-coding genomic regions instead. Here, we review how variants in the non-coding genome of DSD patients can be identified using techniques such as array comparative genomic hybridization (CGH) to detect copy number variants (CNVs), and more recently, whole genome sequencing (WGS). Once a CNV in a patient's non-coding genome is identified, putative regulatory elements such as enhancers need to be determined within these vast genomic regions. We will review the available online tools and databases that can be used to refine regions with potential enhancer activity based on chromosomal accessibility, histone modifications, transcription factor binding site analysis, chromatin conformation, and disease association. We will also review the current in vitro and in vivo techniques available to demonstrate the functionality of the identified enhancers. The review concludes with a clinical update on the enhancers linked to DSD.

In vertebrates, gonadal sex determination is the process by which transcription factors drive the choice between the testicular and ovarian identity of undifferentiated somatic progenitors through activation of 2 different transcriptional programs. Studies in animal models suggest that sex determination always involves sex-specific transcription factors that activate or repress sex-specific genes. These transcription factors control their target genes by recognizing their regulatory elements in the non-coding genome and their binding motifs within their DNA sequence. In the last 20 years, the development of genomic approaches that allow identifying all the genomic targets of a transcription factor in eukaryotic cells gave the opportunity to globally understand the function of the nuclear proteins that control complex genetic programs. Here, the major transcription factors involved in male and female vertebrate sex determination and the genomic profiling data of mouse gonads that contributed to deciphering their transcriptional regulation role will be reviewed.

The mammalian Y chromosome has evolved in many species into a specialized chromosome that contributes to sex development among other male phenotypes. This function is well studied in terms of protein-coding genes. Less is known about the noncoding genome on the Y chromosome and its contribution to both sex development and other traits. Once considered junk genetic material, noncoding RNAs are now known to contribute to the regulation of gene expression and to play an important role in refining cellular functions. The prime examples are noncoding genes on the X chromosome, which mitigate the differential dosage of genes on sex chromosomes. Here, we discuss the evolution of noncoding RNAs on the Y chromosome and the emerging evidence of how micro, long, and circular noncoding RNAs transcribed from the Y chromosome contribute to sex differentiation. We briefly touch on emerging evidence that these noncoding RNAs also contribute to some other important clinical phenotypes in humans.

The role of environmental factors in sexual differentiation in amphibians is not new. The effect of hormones or hormone-like compounds is widely demonstrated. However, the effect of temperature has traditionally been regarded as something anecdotal that occurs in extreme situations and not as a factor to be considered. The data currently available reveal a different situation. Sexual differentiation in some amphibian species can be altered even by small changes in temperature. On the other hand, although not proven, it is possible that temperature is related to the appearance of sex-reversed individuals in natural populations under conditions unrelated to environmental contaminants. According to this, temperature, through sex reversal (phenotypic sex opposed to genetic sex), could play an important role in the turnover of sex-determining genes and in the maintenance of homomorphic sex chromosomes in this group. Accordingly, and given the expected increase in global temperatures, growth and sexual differentiation in amphibians could easily be affected, altering the sex ratio in natural populations and posing major conservation challenges for a group in worldwide decline. It is therefore particularly urgent to understand the mechanism by which temperature affects sexual differentiation in amphibians.

Sex determination and differentiation varies widely across vertebrates, but is most dramatically diverse in fishes. Among fishes sex reversal and sex change are observed in 41 teleost families spanning 7 orders. These sex-changing fish perhaps highlight better than any other system that sex determination is not the narrow and fixed construct we once thought, but a plastic trait that is better viewed as a reaction norm. However, while this stunning transformation is increasingly understood, a fundamental question arises, which is why some fish species have retained this inherent plasticity in sexual fate, while others have not? Here, we explore our current understanding of sex change in fish, some of the factors that permit and constrain sex reversal, and posit that gene duplication and neofunctionalization contribute to the sexual lability observed in fish.

Erectile dysfunction (ED) is one of the most prevalent chronic conditions affecting men. ED can arise from disruptions during development, affecting the patterning of erectile tissues in the penis and/or disruptions in adulthood that impact sexual stimuli, neural pathways, molecular changes, and endocrine signalling that are required to drive erection. Sexual stimulation activates the parasympathetic system which causes nerve terminals in the penis to release nitric oxide (NO). As a result, the penile blood vessels dilate, allowing the penis to engorge with blood. This expansion subsequently compresses the veins surrounding the erectile tissue, restricting venous outflow. As a result, the blood pressure localised in the penis increases dramatically to produce a rigid erection, a process known as tumescence. The sympathetic pathway releases noradrenaline (NA) which causes detumescence: the reversion of the penis to the flaccid state. Androgen signalling is critical for erectile function through its role in penis development and in regulating the physiological processes driving erection in the adult. Interestingly, estrogen signalling is also implicated in penis development and potentially in processes which regulate erectile function during adulthood. Given that endocrine signalling has a prominent role in erectile function, it is likely that exposure to endocrine disrupting chemicals (EDCs) is a risk factor for ED, although this is an under-researched field. Thus, our review provides a detailed description of the underlying biology of erectile function with a focus on the role of endocrine signalling, exploring the potential link between EDCs and ED based on animal and human studies.

Fishes are the only vertebrates that undergo sex change during their lifetime, but even within this group, a unique reproductive strategy is displayed by only 1.5% of the teleosts. This lability in alternating sexual fate is the result of the simultaneous suppression and activation of opposing male and female networks. Here, we provide a brief review summarizing recent advances in our understanding of the environmental cues that trigger sex change and their perception, integration, and translation into molecular cascades that convert the sex of an individual. We particularly focus on molecular events underpinning the complex behavioral and morphological transformation involved in sex change, dissecting the main molecular players and regulatory networks that shape the transformation of one sex into the opposite. We show that histological changes and molecular pathways governing gonadal reorganization are better described than the neuroendocrine basis of sex change and that, despite important advances, information is lacking for the majority of hermaphrodite species. We highlight significant gaps in our knowledge of how sex change takes place and suggest future research directions.

In species with temperature-dependent sex determination (TSD), incubation temperatures regulate the expression of genes involved in gonadal differentiation and determine whether the gonads develop into ovaries or testes. For most species, natural incubation conditions result in transient exposure to thermal cues for both ovarian and testis development, but how individuals respond to this transient exposure varies and can drive variation in the resulting sex ratios. Here, we argue that variation in the timing to respond to temperature cues, or thermal responsiveness, is a trait needing further study. Recent work in the red-eared slider turtle (Trachemys scripta) has found that when embryos experience transient exposure to warm conditions (i.e., heatwaves), some embryos show high responsiveness, requiring only short exposures to commit to ovarian development, while others show low responsiveness, developing testes even after more extended exposures to warm conditions. We discuss how maternal estrogens might influence thermal responsiveness for organisms that develop under thermal fluctuations. Examining the interplay of molecular responses to more subtle thermal and endocrine environments may reveal significant insights into the process of sex determination in species with TSD.

Germline development varies significantly across metazoans. However, mammalian primordial germ cell (PGC) development has key conserved landmarks, including a critical period of epigenetic reprogramming that precedes sex-specific differentiation and gametogenesis. Epigenetic alterations in the germline are of unique importance due to their potential to impact the next generation. Therefore, regulation of, and by, the non-coding genome is of utmost importance during these epigenomic events. Here, we detail the key chromatin changes that occur during mammalian PGC development and how these interact with the expression of non-coding RNAs alongside broader epitranscriptomic changes. We identify gaps in our current knowledge, in particular regarding epigenetic regulation in the human germline, and we highlight important areas of future research.

Studying environmental sex determination (ESD) in cichlids provides a phylogenetic and comparative approach to understand the evolution of the underlying mechanisms, their impact on the evolution of the overlying systems, and the neuroethology of life history strategies. Natural selection normally favors parents who invest equally in the development of male and female offspring, but evolution may favor deviations from this 50:50 ratio when environmental conditions produce an advantage for doing so. Many species of cichlids demonstrate ESD in response to water chemistry (temperature, pH, and oxygen concentration). The relative strengths of and the exact interactions between these factors vary between congeners, demonstrating genetic variation in sensitivity. The presence of sizable proportions of the less common sex towards the environmental extremes in most species strongly suggests the presence of some genetic sex-determining loci acting in parallel with the ESD factors. Sex determination and differentiation in these species does not seem to result in the organization of a final and irreversible sexual fate, so much as a life-long ongoing battle between competing male- and female-determining genetic and hormonal networks governed by epigenetic factors. We discuss what is and is not known about the epigenetic mechanism behind the differentiation of both gonads and sex differences in the brain. Beyond the well-studied tilapia species, the 2 best-studied dwarf cichlid systems showing ESD are the South American genus Apistogramma and the West African genus Pelvicachromis. Both species demonstrate male morphs with alternative reproductive tactics. We discuss the further neuroethology opportunities such systems provide to the study of epigenetics of alternative life history strategies and other behavioral variation.