The molecular pathways underlying early gonadal development

Abstract

The body of knowledge surrounding reproductive development spans the fields of genetics, anatomy, physiology and biomedicine, to build a comprehensive understanding of the later stages of reproductive development in humans and animal models. Despite this, there remains much to learn about the bi-potential progenitor structure that the ovary and testis arise from, known as the genital ridge (GR). This tissue forms relatively late in embryonic development and has the potential to form either the ovary or testis, which in turn produce hormones required for development of the rest of the reproductive tract. It is imperative that we understand the genetic networks underpinning GR development if we are to begin to understand abnormalities in the adult. This is particularly relevant in the contexts of disorders of sex development (DSDs) and infertility, two conditions that many individuals struggle with worldwide, with often no answers as to their aetiology. Here, we review what is known about the genetics of GR development. Investigating the genetic networks required for GR formation will not only contribute to our understanding of the genetic regulation of reproductive development, it may in turn open new avenues of investigation into reproductive abnormalities and later fertility issues in the adult.

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

“…Subsequently, by five weeks post-conception, primordial germ cells migrate from the yolk sac to the urogenital ridge. Several genes including NR5A1 (also known as SF1), WT1, EMX2, and LHX9 are required for the formation of the bipotential gonadal ridge in humans [5,6].…”

The embryonic ontogeny of the gonadal somatic cells in mice and monkeys

“…The formation of sexual dimorphism involves critical and pervasive events in sexually reproducing animals, thereby ensuring reproductive success. The gonads play a central role in such processes, because their differentiation into either ovaries or testes subsequently dictates the overall sex characteristics of the individual by regulating development of the external and internal sex organs and the brain via sex hormones (Capel, 2017;Yang et al, 2018). The embryonic gonads initially form as sexually bipotent structures known as genital ridges (GRs), which consist of GR progenitor cells (GPCs).…”

“…Although most previous studies have focused on the cellular, genetic, and epigenetic cues that direct the formation of gonadal sexual dimorphism from GRs (Capel, 2017), the ontogeny of bipotential gonads and the accompanying molecular events driving their development remain poorly understood, particularly in humans and non-human primates. The formation of the GR starts around embryonic day (E) 10.5 through the proliferation of the coelomic epithelium (CE) at the ventromedial aspect of mesonephros, a process that appears to be accompanied by the dissolution of basement membranes and the epithelial-tomesenchymal transition (EMT) (Karl and Capel, 1998;Kusaka et al, 2010;Yang et al, 2018). Prior studies have identified key genetic determinants of nascent GR formation, including Gata4, Nr5a1, Lhx9, Emx2, Six1/4, Cbx2, and Tcf21 (Birk et al, 2000;Cui et al, 2004;Fujimoto et al, 2013;Hu et al, 2013;Kusaka et al, 2010;Luo et al, 1994;Miyamoto et al, 1997).…”

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

“…During embryonic stages in mammals, the gonadal ridge develops as a thickening of the coelomic epithelium, on the ventromedial surface of the mesonephric kidney, marking the formation of the gonadal primordium [ 18 ]. Coordinated proliferation of the coelomic epithelial cells, delamination and ingression of those cells results in the further development of the primordium [ 143 ]. In mammals, ingressing cells are the undifferentiated precursors of the supporting and steroidogenic cell lineages ( Figure 1 ) [ 17 ].…”