Stay on the road: from germ cell specification to gonadal colonization in mammals

Abstract

The founder cells of the gametes are primordial germ cells (PGCs). In mammals, PGCs are specified early during embryonic development, at the boundary between embryonic and extraembryonic tissue, long before their later residences, the gonads, have developed. Despite the differences in form and behaviour when differentiated into oocytes or sperm cells, in the period between specification and gonadal colonization, male and female PGCs are morphologically indistinct and largely regulated by similar mechanisms. Here, we compare different modes and mechanisms that lead to the formation of PGCs, putting in context protocols that are in place to differentiate both human and mouse pluripotent stem cells into PGC-like cells. In addition, we review important aspects of the migration of PGCs to the gonadal ridges, where they undergo further sex-specific differentiation. Defects in migration need to be effectively corrected, as misplaced PGCs can become tumorigenic. Concluding, a combination of in vivo studies and the development of adequate innovative in vitro models, ensuring both robustness and standardization, are providing us with the tools for a greater understanding of the first steps of gametogenesis and to develop disease models to study the origin of germ cell tumours. This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.

The journey of a generation: advances and promises in the study of primordial germ cell migration

“…In many animals, such as fruit flies, sea urchins and frogs, the journey begins with the passive translocation of PGCs during gastrulation ( Figs 1 and 2A ) ( Nishiumi et al, 2005 ; Yajima and Wessel, 2012 ; DeGennaro et al, 2011 ). In the mouse, a combination of active and passive movements seems to facilitate internalization as newly specified mouse PGCs initially display features of active migration, but, once associated with the hindgut epithelium, they move in synchrony with the gastrulating hindgut ( Anderson et al, 2000 ; Spiegelman and Bennett, 1973 ; Kanamori et al, 2019 ; Roelen and Chuva de Sousa Lopes, 2022 ). During or shortly after passive translocation, PGCs are often located within the endoderm, as observed in the fruit fly, sea urchin, mouse, rat and marmoset monkey ( Kamimura et al, 1980 ; Molyneaux et al, 2001 ; Kemper and Peters, 1987 ; Aeckerle et al, 2015 ; Warrior, 1994 ; Jaglarz and Howard, 1994 ; Campanale et al, 2014 ) ( Fig.…”

Bioengineered 3D Ovarian Models as Paramount Technology for Female Health Management and Reproduction

“…For this, Pandolfi and colleagues differentiated induced PSCs (iPSCs) obtained from two infertile individuals diagnosed with primary ovarian insufficiency (POI) and their respective MA twins into hPGCLCs, but there were no significant differences between hPGCLCs obtained from the infertile and fertile twin in the two pairs studied [34]. They then tested whether iPSCs from each twin could generate amniotic sac-like structures, since both twins shared one single amnion during gestation and human PGCs are thought to originate from the amnion [35]. Regardless of the fertility condition of the donors, all iPSC lines formed both amniotic ectoderm-like cells and hPGCLCs.…”

Endometrial TGFβ signaling fosters early pregnancy development by remodeling the fetomaternal interface

“…36,37 The TGFβ signaling pathway directs the specification of germ cell lineage during embryonic development and is crucial for ovarian and testicular function in adult mammals. [38][39][40][41] In the pituitary, for example, follicle stimulating hormone (FSH), a TGFβ family ligand, is a central driver of the hypothalamic pituitary gonadal axis and controls integral processes related to male and female reproductive function. 42,43 Other ligands, such as activin and anhibin are critical for gonadal function, as demonstrated by the defects in genetic mouse models.…”