Origin, specification and differentiation of a rare supporting-like lineage in the developing mouse gonad

Gonadal sex determination represents a unique model for studying cell fate decisions. However, a complete understanding of the different cell lineages forming the developing testis and ovary remains elusive. Here, we investigated the origin, specification and subsequent sex-specific differentiation of a previously uncharacterized population of supporting-like cells (SLC) in the developing mouse gonads. The SLC lineage is closely related to the coelomic epithelium and specified as early as E10.5, making it the first somatic lineage to be specified in the bipotential gonad. SLC progenitors are localized within the genital ridge at the interface with the mesonephros and initially co-express Wnt4 and Sox9. SLCs become sexually dimorphic around E12.5, progressively acquire a Sertoli- or granulosa-like identity and contribute to the formation of the rete testis and rete ovarii. Finally, we found that WNT4 is a crucial regulator of the SLC lineage and is required for the formation of the rete testis.

Diverse Regulation but Conserved Function: SOX9 in Vertebrate Sex Determination

Sex determination occurs early during embryogenesis among vertebrates. It involves the differentiation of the bipotential gonad to ovaries or testes by a fascinating diversity of molecular switches. In most mammals, the switch is SRY (sex determining region Y); in other vertebrates it could be one of a variety of genes including Dmrt1 or dmy. Downstream of the switch gene, SOX9 upregulation is a central event in testes development, controlled by gonad-specific enhancers across the 2 Mb SOX9 locus. SOX9 is a ‘hub’ gene of gonadal development, regulated positively in males and negatively in females. Despite this diversity, SOX9 protein sequence and function among vertebrates remains highly conserved. This article explores the cellular, morphological, and genetic mechanisms initiated by SOX9 for male gonad differentiation.

Loss of dmrt1 restores female fates in the absence of cyp19a1a but not rbpms2

Sex determination and differentiation is a complex process regulated by multiple factors, including factors from the germline or surrounding somatic tissue. In zebrafish, sex-determination begins with establishment of a bipotential gonad that undergoes sex-specific differentiation and maintenance to form the functional adult gonad. However, the relationships among these factors are not fully understood. Here we identify potential Rbpms2 targets and apply genetic epistasis experiments to decipher the genetic hierarchy of regulators of sex-specific differentiation. We provide evidence that the critical female factor, rbpms2 is epistatic to the male factor dmrt1 in terms of adult sex. Moreover, Rbpms2’s role in promoting female fates extends beyond repression of Dmrt1, as Rbpms2 is essential for female differentiation even in the absence of Dmrt1. In contrast, female fates can be restored in mutants lacking cyp19a1a in the absence of dmrt1. Taken together this work indicates that Cyp19a1a-mediated suppression of Dmrt1 is key to establish a bipotential gonad and initiate female fate acquisition, possibly by promoting rbpms2. Then, after female fate specification, Cyp19a1a regulates subsequent oocyte maturation and sustains female fates independent of Dmrt1 repression.Author SummaryWe show that cyp19a1a-mediated suppression of dmrt1 establishes a bipotential gonad and female fate acquisition, possibly through rbpms2 which is required for female fates, even in the absence of Dmrt1.

Socio-medical burden of managing a Nigerian child with 46XY male disorder of sex differentiation: A Case Report

Phenotypic expression of the male internal and external genitalia is due largely to the interplay between the proper differentiation of the bipotential gonad, the production of testosterone from the Leydig cells and the response of the undifferentiated external genitalia to Dihydrotestosterone. When any of the pathways involved in the mechanisms described above are distorted, it results in the 46 XY Disorder of Sex Differentiation (DSD).The incidence of 46 XY DSD ranges from 20 to 41% among the cases of Disorder of Sex Differentiation (DSD) in Nigeria, though there is a paucity of data on this condition. This report describes an under-virilized genetically male child who presented with ambiguous genitalia in the neonatal period and was subsequently diagnosed as SRY positive 46 XY DSD with reduced testosterone synthesis. This report is necessitated by the need to create awareness and highlight the relevant medico-social challenges in the management of DSD in a resource-poor setting.

WOMEN IN REPRODUCTIVE SCIENCE: To be or not to be a testis

Work that established the testis as the driver of male development, and the Y chromosome as the bearer of the male-determining gene, established a working model, and set the stage for the molecular age of mammalian sex determination. The discovery and characterization of Sry/SRY at the top of the hierarchy in mammals launched the field in two major directions. The first was to identify the downstream transcription factors and other molecular players that drive the bifurcation of Sertoli and granulosa cell differentiation. The second major direction was to understand organogenesis of the early bipotential gonad, and how divergence of its two distinct morphogenetic pathways (testis and ovary) is regulated at the cellular level. This review will summarize the early discoveries soon after Sry was identified and focus on my study of the gonad as a model of organogenesis.

Neural crest-derived neurons invade the ovary but not the testis during mouse gonad development

Testes and ovaries undergo sex-specific morphogenetic changes and adopt strikingly different morphologies, despite the fact that both arise from a common precursor, the bipotential gonad. Previous studies showed that recruitment of vasculature is critical for testis patterning. However, vasculature is not recruited into the early ovary. Peripheral innervation is involved in patterning development of many organs but has been given little attention in gonad development. In this study, we show that while innervation in the male reproductive complex is restricted to the epididymis and vas deferens and never invades the interior of the testis, neural crest-derived innervation invades the interior of the ovary around E16.5. Individual neural crest cells colonize the ovary, differentiate into neurons and glia, and form a dense neural network within the ovarian medulla. Using a sex-reversing mutant mouse line, we show that innervation is specific to ovary development, is not dependent on the genetic sex of gonadal or neural crest cells, and may be blocked by repressive guidance signals elevated in the male pathway. This study reveals another aspect of sexually dimorphic gonad development, establishes a precise timeline and structure of ovarian innervation, and raises many questions for future research.

How Australian mammals contributed to our understanding of sex determination and sex chromosomes

Marsupials and monotremes can be thought of as independent experiments in mammalian evolution. The discovery of the human male-determining gene, SRY, how it works, how it evolved and defined our sex chromosomes, well illustrates the value of comparing distantly related animals and the folly of relying on humans and mice for an understanding of the most fundamental aspects of mammalian biology. The 25th anniversary of the discovery of SRY seems a good time to review the contributions of Australian mammals to these discoveries. The discovery of the mammalian sex determining gene, SRY, was a milestone in the history of human genetics. SRY opened up investigations into the pathway by which the genital ridge (bipotential gonad) becomes a testis. Studies of Australian mammals were important in the story of the discovery of SRY, not only in refuting the qualifications of the first candidate sex-determining gene, but also in confirming the ubiquity of SRY and raising questions as to how it works. Studies in marsupials also led to understanding of how SRY evolved from a gene on an autosome with functions in the brain and germ cells, and to identifying the ancestors of other genes on the human Y. The discovery that platypus have sex chromosomes homologous, not to the human XY, but to the bird ZW, dated the origin of the therian SRY and the XY chromosomes it defined. This led to important new models of how our sex chromosomes function, how they evolved, and what might befall this gene and the Y chromosome it defines.