Sexual Development最新文献

Background: The anti-müllerian hormone (Amh) pathway is crucial for sexual development in teleosts. A male-specific duplicate of anti-müllerian hormone (amhby) was previously identified as the northern pike (Esox lucius) master sex determination gene. However, the role of its putative cognate receptor, i.e., the anti-müllerian hormone receptor type 2 (amhrII) was unclear in this species.

Objective: Here, we investigated the role of amhrII during sexual development of northern pike.

Method: We generated stable mutants with deletions in exon 9 of amhrII, inactivating the AmhrII protein using a CRISPR-Cas9-mediated gene knockout strategy.

Result: The inactivation of amhrII in northern pike results in a high level of male-to-female sex reversal.

Conclusion: This result demonstrates that amhrII is necessary for male sexual development in northern pike and supports the idea that AmhrII is a conserved regulator of the teleosts sex differentiation network.

Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.

Introduction: The aim of this retrospective study was to verify the association between the time of diagnosis and initial and final sex assignment in a disorder of sex development (DSD) diagnostic group, looking at the age of the patients at first visit, severity of genital ambiguity, and karyotype.

Methods: The time of diagnosis was divided into 3 groups: before 2000, between 2000 and 2006, and after 2006. Data were categorized and analyzed using the χ2 test with α < 0.05.

Results: A total of 567 cases were analyzed; 307 were assigned as male, 135 as female, and 125 remained undefined at the first visit. After clinical and laboratory evaluations, 369 patients were male and 198 were female. Neither initial nor final sex assignment proportions changed over time, but there were significant differences in the age at first visit, with referral occurring at an earlier age, as well as more severe genital ambiguity presentations, a higher proportion of sex chromosome aberrations, and a lower frequency of 46,XX DSD cases. This occurred both in the sample as a whole (567 cases) and in the group of 125 patients without definitive sex assignment at the first visit. The results were similar when only 284 patients aged less than 12 months at the first visit were analyzed.

Discussion/conclusion: Over time, there were no changes in sex assignment proportions, but there was an increased awareness of the need for early referral and changes in clinical, cytogenetic, and diagnostic aspects.

Puberty is a complex transitional phase in which reproductive capacity is achieved. There is a very wide variation in the age range of the onset of puberty, which follows a familial, ethnic, and sex pattern. The hypothalamic-pituitary-gonadal axis and several genetic, environmental, and nutritional factors play an important role in the onset of and throughout puberty. Recently, there has been significant progress in identifying factors that affect normal pubertal timing. Different studies have identified single nucleotide polymorphisms (SNPs) that affect pubertal timing in both sexes and across ethnic groups. Single genes are implicated in both precocious and delayed puberty, and epigenetic mechanisms have been suggested to affect the development and function of the GnRH neuronal network and responsiveness of end organs. All these factors can influence normal puberty timing, precocious puberty, and delayed puberty. The objective of this review is to describe recent findings related to the genetic and epigenetic control of puberty and highlight the need to deepen the knowledge of the regulatory mechanisms of this process in the normal and abnormal context.

Introduction: Sex determination in eutherian mammals is controlled by the Y-linked gene Sry, which drives the formation of testes in male embryos. Despite extensive study, the genetic steps linking Sry action and male sex determination remain largely unknown. Here, we focused on Mmd2, a gene that encodes a member of the progestin and adipoQ receptor (PAQR) family. Mmd2 is expressed during the sex-determining period in XY but not XX gonads, suggesting a specific role in testis development.

Methods: We used CRISPR to generate mouse strains deficient in Mmd2 and its 2 closely related PAQR family members, Mmd and Paqr8, which are also expressed during testis development. Following characterization of Mmd2 expression in the developing testis, we studied sex determination in embryos from single knockout as well as Mmd2;Mmd and Mmd2;Paqr8 double knockout lines using quantitative RT-PCR and immunofluorescence.

Results: Analysis of knockout mice deficient in Sox9 and Nr5a1 revealed that Mmd2 operates downstream of these known sex-determining genes. However, fetal testis development progressed normally in Mmd2-null embryos. To determine if other genes might have compensated for the loss of Mmd2, we analyzed Paqr8 and Mmd-null embryos and confirmed that in both knockout lines, sex determination occurred normally. Finally, we generated Mmd2;Mmd and Mmd2;Paqr8 double-null embryos and again observed normal testis development.

Discussion: These results may reflect functional redundancy among PAQR factors, or their dispensability in gonadal development. Our findings highlight the difficulties involved in identifying genes with a functional role in sex determination and gonadal development through expression screening and loss-of-function analyses of individual candidate genes and may help to explain the paucity of genes in which variations have been found to cause human disorders/differences of sex development.