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Fanconi Anemia (FA) is a genomic instability syndrome resulting in aplastic anemia, developmental abnormalities, and predisposition to hematological and other solid organ malignancies. Mutations in genes that encode proteins of the FA pathway fail to orchestrate the repair of DNA damage caused by DNA interstrand crosslinks. Zebrafish harbor homologs for nearly all known FA genes. We used multiplexed CRISPR/Cas9-mediated mutagenesis to generate loss-of-function mutants for 17 FA genes: fanca, fancb, fancc, fancd1/brca2, fancd2, fance, fancf, fancg, fanci, fancj/brip1, fancl, fancm, fancn/palb2, fanco/rad51c, fancp/slx4, fancq/ercc4, fanct/ube2t, and two genes encoding FA-associated proteins: faap100 and faap24. We selected two indel mutations predicted to cause premature truncations for all but two of the genes, and a total of 36 mutant lines were generated for 19 genes. Generating two independent mutant lines for each gene was important to validate their phenotypic consequences. RT-PCR from homozygous mutant fish confirmed the presence of transcripts with indels in all genes. Interestingly, 4 of the indel mutations led to aberrant splicing, which may produce a different protein than predicted from the genomic sequence. Analysis of RNA is thus critical in proper evaluation of the consequences of the mutations introduced in zebrafish genome. We used fluorescent reporter assay, and western blots to confirm loss-of-function for several mutants. Additionally, we developed a DEB treatment assay by evaluating morphological changes in embryos and confirmed that homozygous mutants from all the FA genes that could be tested (11/17), displayed hypersensitivity and thus were indeed null alleles. Our multiplexing strategy helped us to evaluate 11 multiple gene knockout combinations without additional breeding. Homozygous zebrafish for all 19 single and 11 multi-gene knockouts were adult viable, indicating FA genes in zebrafish are generally not essential for early development. None of the mutant fish displayed gross developmental abnormalities except for fancp-/- fish, which were significantly smaller in length than their wildtype clutch mates. Complete female-to-male sex reversal was observed in knockouts for 12/17 FA genes, while partial sex reversal was seen for the other five gene knockouts. All adult females were fertile, and among the adult males, all were fertile except for the fancd1 mutants and one of the fancj mutants. We report here generation and characterization of zebrafish knockout mutants for 17 FA disease-causing genes, providing an integral resource for understanding the pathophysiology associated with the disrupted FA pathway.

Differences of sex development are conditions with discrepancies between chromosomal, gonadal and phenotypic sex. In congenital hypogonadotropic hypogonadism, a lack of gonadotropin activity results primarily in the absence of pubertal development with prenatal sex development being (almost) unaffected in most patients. To expedite progress in the care of people affected by differences of sex development and congenital hypogonadotropic hypogonadism, the European Union has funded a number of scientific networks. Two Actions of the Cooperation of Science and Technology (COST) programmes — DSDnet (BM1303) and GnRH Network (BM1105) — provided the framework for ground-breaking research and allowed the development of position papers on diagnostic procedures and special laboratory analyses as well as clinical management. Both Actions developed educational programmes to increase expertise and promote interest in this area of science and medicine. In this Perspective article, we discuss the success of the COST Actions DSDnet and GnRH Network and the European Reference Network for Rare Endocrine Conditions (Endo–ERN), and provide recommendations for future research.

Clinical studies and mathematical models predict that, to achieve malaria elimination, combination therapies will need to incorporate drugs that block the transmission of Plasmodium falciparum sexual stage parasites to mosquito vectors. Efforts to measure the activity of existing antimalarials on intraerythrocytic sexual stage gametocytes and identify transmission-blocking agents have, until now, been hindered by a lack of quantitative assays. Here, we report an experimental system using P. falciparum lines that stably express gametocyte-specific GFP-luciferase reporters, which enable the assessment of dose- and time-dependent drug action on gametocyte maturation and transmission. These studies reveal activity of the first-line antimalarial dihydroartemisinin and the partner drugs lumefantrine and pyronaridine against early gametocyte stages, along with moderate inhibition of mature gametocyte transmission to Anopheles mosquitoes. The other partner agents monodesethyl-amodiaquine and piperaquine showed activity only against immature gametocytes. Our data also identify methylene blue as a potent inhibitor of gametocyte development across all stages. This thiazine dye almost fully abolishes P. falciparum transmission to mosquitoes at concentrations readily achievable in humans, highlighting the potential of this chemical class to reduce the spread of malaria.

Since females grow faster in penaeid shrimp, all-female aquaculture was proposed. Environmental conditions in the Pacific white shrimp were not found to affect genetic sex determination (ZZ/ZW system). The androgenic gland–secreting insulin-like androgenic gland hormone is a key controlling factor in crustacean male differentiation. However, functional sex reversal (neo-male) in penaeid shrimp has not yet been achieved by manipulating the insulin-like androgenic gland hormone–sexual switch. Therefore, understanding the molecular mechanisms of gonadal differentiation may help build appropriate tools to generate neo-male for all-female breeding. This study describes the potential role of the novel penaeid-specific testicular zinc finger protein (pTZFP) in the gonads of Pacific white shrimp. First, pTZFP transcripts show a male-bias expression pattern in undifferentiated gonads, which is then exclusively expressed in the testis and absent or slightly expressed in the ovary and other tissues. Besides, the knockdown of pTZFP in undifferentiated males results in smaller testes but no sex reversal. Immunohistochemical staining of proliferating cell nuclear antigen further confirmed that the smaller testes in pTZFP-deficient males are due to the lower proliferating activity of spermatogonia. These data reveal that pTZFP may be involved in testicular development but have fewer effects on gonadal differentiation. Moreover, testicular pTZFP transcription levels were not reduced with estradiol-17β (E2) administration or AG excision. Therefore, our data suggest that pTZFP may regulate testicular development through downstream genes regulating spermatogonia proliferation. Moreover, our data provide an appropriate molecular marker for identifying the sex of undifferentiated gonads. Summary Sentence pTZFP participates in testicular development by regulating spermatogonia proliferation, and its male-biased expression profile provides an appropriate molecular marker for identifying the critical window of gonadal sex differentiation in penaeid shrimp. Graphical Abstract

Background Exploring the physiological and molecular mechanisms underlying goat sexual maturation can enhance breeding practices and optimize reproductive efficiency and is therefore substantially important for practical breeding purposes. As an essential neuroendocrine organ in animals, the hypothalamus is involved in sexual development and other reproductive processes in female animals. Although microRNAs (miRNAs) have been identified as significant regulators of goat reproduction, there is a lack of research on the molecular regulatory mechanisms of hypothalamic miRNAs that are involved in the sexual development of goats. Therefore, we examined the dynamic changes in serum hormone profiles and hypothalamic miRNA expression profiles at four developmental stages (1 day (neonatal, D1, n  = 5), 2 months (prepubertal, M2, n  = 5), 4 months (sexual maturity, M4, n  = 5), and 6 months (breeding period, M6, n  = 5)) during sexual development in Jining grey goats. Results Transcriptome analysis revealed 95 differentially expressed miRNAs (DEMs) in the hypothalamus of goats across the four developmental stages. The target genes of these miRNAs were significantly enriched in the GnRH signalling pathway, the PI3K-Akt signalling pathway, and the Ras signalling pathway ( P  < 0.05). Additionally, 16 DEMs are common among the M2 vs. D1, M4 vs. D1, and M6 vs. D1 comparisons, indicating that the transition from D1 to M2 represents a potentially critical period for sexual development in Jining grey goats. The bioinformatics analysis results indicate that miR-193a/miR-193b-3p-Annexin A7 ( ANXA7 ), miR-324-5p-Adhesion G protein-coupled receptor A1 ( ADGRA1 ), miR-324-3p-Erbb2 receptor tyrosine kinase 2 ( ERBB2 ), and miR-324-3p-Rap guanine nucleotide exchange factor 3 ( RAPGEF3 ) are potentially involved in biological processes such as hormone secretion, energy metabolism, and signal transduction. In addition, we further confirmed that miR-324-3p targets the regulatory gene RAPGEF3 . Conclusion These results further enrich the expression profile of hypothalamic miRNAs in goats and provide important insights for studying the regulatory effects of hypothalamic miRNAs on the sexual development of goats after birth.

Sexual reproduction generates new gene combinations and novel phenotypic traits and facilitates evolution. Induction of sexual development in fungi is often regulated by environmental conditions, such as the presence of light and nutrients. The velvet protein complex coordinates internal cues and environmental signals to regulate development. We have found that VE-1, a component of the velvet complex, regulates transcription during sexual development in the fungus Neurospora crassa . VE-1 regulates the transcription of many genes, including those involved in mitogen-activated protein kinase (MAPK) signaling pathways that are essential in the regulation of sexual development, and regulates the activity of the MAPK pathway. Our findings provide valuable insights into how fungi respond to environmental signals and integrate them into their reproductive processes.

Limited empirical evidence exists regarding longitudinal connections between parenting during childhood and adolescents’ sexual development. Using structural equation mediation modeling, this study examined how mothers’ parenting practices during childhood (ages 8 to 11) directly related to adolescent sexual outcomes (ages 12 to 16) and whether relationships were mediated by parenting practices persisting over time. Two waves of data were used from a large longitudinal national sample including 687 mother-adolescent pairs (Mage = 10.02, SD = 1.15, 50% female, 64% White) in 2002 and 2007. For boys, mothers’ knowledge of whereabouts and warmth during childhood had negative direct connections to later frequency of intercourse. However, no parallel connections were found for girls. For both boys and girls, mothers’ warmth during childhood was associated with an increased likelihood of sexual debut in adolescence. The findings highlight that parenting practices during childhood directly and indirectly (through parenting trajectories) shape sexual development of children.

Peer groups influence the emergence of sexual behaviors in adolescence, but many details regarding the mechanisms underlying these effects have yet to be described. We examined the phenotypic, genetic, and environmental links between both antisocial and prosocial peer characteristics, and several sexual behaviors from middle childhood to late adolescence (ages 11, 14, and 17 years) using a longitudinal twin sample ( N  = 3762). Antisocial peers predicted greater engagement in both normative (e.g., dating) and non-normative (e.g., early sexual intercourse) sexual behaviors, while prosocial peers were associated with a lower likelihood of engaging in non-normative sexual behaviors. Reciprocal effects were also observed such that early sexual experiences were associated with a more antisocial and less prosocial peer groups later in adolescence. Behavioral genetic models indicated that most of the overlap between peer group characteristics and sexual behavior was due to shared environmental influences. That is, some features of the adolescent environment exert a press toward (or against) antisocial peers and sexual behaviors. Together, the results extend the existing literature by highlighting the ways through which peer affiliations are related to sexual development in adolescence.

Transposable elements are endogenous DNA sequences able to integrate into and multiply within genomes. They constitute a major source of genetic innovations, as they can not only rearrange genomes but also spread ready-to-use regulatory sequences able to modify host gene expression, and even can give birth to new host genes. As their evolutionary success depends on their vertical transmission, transposable elements are intrinsically linked to reproduction. In organisms with sexual reproduction, this implies that transposable elements have to manifest their transpositional activity in germ cells or their progenitors. The control of sexual development and function can be very versatile, and several studies have demonstrated the implication of transposable elements in the evolution of sex. In this review, we report the functional and evolutionary relationships between transposable elements and sexual reproduction in animals. In particular, we highlight how transposable elements can influence expression of sexual development genes, and how, reciprocally, they are tightly controlled in gonads. We also review how transposable elements contribute to the organization, expression and evolution of sexual development genes and sex chromosomes. This underscores the intricate co-evolution between host functions and transposable elements, which regularly shift from a parasitic to a domesticated status useful to the host.

Wolffian ducts (WDs) are the embryonic structures that form the male internal genitalia. These ducts develop in both the male and female embryo. However, in the female they subsequently regress, whereas in the male they are stabilised by testosterone. The WDs then develop into separate but contiguous organs, the epididymis, vas deferens and seminal vesicles. Recently, considerable progress has been made in identifying genes that are involved in these different stages of development which is described in this review. In addition, WD development in (atypical forms of) cystic fibrosis and intersex disorders, such as the complete androgen insensitivity syndrome, 17beta-hydroxysteroid dehydrogenase deficiency and LH-receptor defects, is discussed. The apparent increase in male reproductive tract disorders is briefly discussed from the perspective of the potential endocrine-disrupting effects of the numerous chemicals in the environment to which the developing male foetus can be exposed.