The meiosis-specific chromosomal events of homolog pairing, synapsis, and recombination occur over an extended meiotic prophase I that is many times longer than prophase of mitosis. Here we show that, in mice, maintenance of an extended meiotic prophase I requires the gene Meioc, a germ-cell specific factor conserved in most metazoans. In mice, Meioc is expressed in male and female germ cells upon initiation of and throughout meiotic prophase I. Mouse germ cells lacking Meioc initiate meiosis: they undergo pre-meiotic DNA replication, they express proteins involved in synapsis and recombination, and a subset of cells progress as far as the zygotene stage of prophase I. However, cells in early meiotic prophase—as early as the preleptotene stage—proceed to condense their chromosomes and assemble a spindle, as if having progressed to metaphase. Meioc-deficient spermatocytes that have initiated synapsis mis-express CYCLIN A2, which is normally expressed in mitotic spermatogonia, suggesting a failure to properly transition to a meiotic cell cycle program. MEIOC interacts with YTHDC2, and the two proteins pull-down an overlapping set of mitosis-associated transcripts. We conclude that when the meiotic chromosomal program is initiated, Meioc is simultaneously induced so as to extend meiotic prophase. Specifically, MEIOC, together with YTHDC2, promotes a meiotic (as opposed to mitotic) cell cycle program via post-transcriptional control of their target transcripts.

The developmental relationship between the posterior embryonic and extraembryonic regions of the mammalian gastrula is poorly understood. Although many different cell types are deployed within this region, only the primordial germ cells (PGCs) have been closely studied. Recent evidence has suggested that the allantois, within which the PGCs temporarily take up residence, contains a pool of cells, called the Allantoic Core Domain (ACD), critical for allantoic elongation to the chorion. Here, we have asked whether the STELLA-positive cells found within this region, thought to be specified PGCs, are actually part of the ACD and to what extent they, and other ACD cells, contribute to the allantois and fetal tissues. To address these hypotheses, STELLA was immunolocalized to the mouse gastrula between Early Streak (ES) and 12-somite pair (-s) stages (~6.75 – 9.0 days post coitum, dpc) in histological sections. STELLA was found in both the nucleus and cytoplasm in a variety of cell types, both within and outside of the putative PGC trajectory. Fate-mapping the headfold-stage (~7.75 – 8.0 dpc) posterior region, by which time PGCs are thought to be segregated into a distinct lineage, revealed that the STELLA-positive proximal ACD and intraembryonic posterior primitive streak (IPS) contributed to a wide range of somatic tissues that encompassed derivatives of the three primary germ layers. This contribution included STELLA-positive cells localizing to tissues both within and outside of the putative PGC trajectory. Thus, while STELLA may identify a subpopulation of cells destined for the PGC lineage, our findings reveal that it may be part of a broader niche that encompasses the ACD and through which the STELLA population may contribute cells to a wide variety of posterior tissues of the mouse gastrula.

Retinoic acid (RA), a derivative of vitamin A, is critical for the production of oocytes and sperm in mammals. These gametes derive from primordial germ cells, which colonize the nascent gonad, and later undertake sexual differentiation to produce oocytes or sperm. During fetal development, germ cells in the ovary initiate meiosis in response to RA, whereas those in the testis do not yet initiate meiosis, as they are insulated from RA, and undergo cell cycle arrest. After birth, male germ cells resume proliferation and undergo a transition to spermatogonia, which are destined to develop into haploid spermatozoa via spermatogenesis. Recent findings indicate that RA levels change periodically in adult testes to direct not only meiotic initiation, but also other key developmental transitions to ensure that spermatogenesis is precisely organized for the prodigious output of sperm. This review focuses on how female and male germ cells develop in the ovary and testis, respectively, and the role of RA in this process.

How the fetal-placental arterial connection is made and positioned relative to the embryonic body axis, thereby ensuring efficient and directed blood flow to and from the mother during gestation, is not known. Here we use a combination of genetics, timed pharmacological inhibition in living mouse embryos, and three-dimensional modeling to link two novel architectural features that, at present, have no status in embryological atlases. The allantoic core domain (ACD) is the extraembryonic extension of the primitive streak into the allantois, or preumbilical tissue; the vessel of confluence (VOC), situated adjacent to the ACD, is an extraembryonic vessel that marks the site of fetal-placental arterial union. We show that genesis of the fetal-placental connection involves the ACD and VOC in a series of steps, each one dependent upon the last. In the first, Brachyury (T) ensures adequate extension of the primitive streak into the allantois, which in turn designates the allantoic-yolk sac junction. Next, the streak-derived ACD organizes allantoic angioblasts to the axial junction; upon signaling from Fibroblast Growth Factor Receptor-1 (FGFR1), these endothelialize and branch, forming a sprouting VOC that unites the umbilical and omphalomesenteric arteries with the fetal dorsal aortae. Arterial union is followed by the appearance of the medial umbilical roots within the VOC, which in turn designate the correct axial placement of the lateral umbilical roots/common iliac arteries. In addition, we show that the ACD and VOC are conserved across Placentalia, including humans, underscoring their fundamental importance in mammalian biology. We conclude that T is required for correct axial positioning of the VOC via the primitive streak/ACD, while FGFR1, through its role in endothelialization and branching, further patterns it. Together, these genetic, molecular and structural elements safeguard the fetus against adverse outcomes that can result from vascular mispatterning of the fetal-placental arterial connection.

No abstract

Interferon-induced transmembrane protein 3 (IFITM3; FRAGILIS; MIL-1) is part of a larger family of important small interferon-induced transmembrane genes and proteins involved in early development, cell adhesion, and cell proliferation, and which also play a major role in response to bacterial and viral infections and, more recently, in pronounced malignancies (Siegrist et al., 2011). IFITM3, together with tissue-nonspecific alkaline phosphatase (TNAP), PRDM1, and STELLA, has been claimed to be a hallmark of segregated primordial germ cells (PGCs) (Saitou et al., 2002). However, whether IFITM3, like STELLA, is part of a broader stem/progenitor pool that builds the posterior region of the mouse conceptus (Mikedis and Downs, 2012), is obscure. To discover the whereabouts of IFITM3 during mouse gastrulation (~E6.5-9.0), systematic immunohistochemical analysis was carried out at closely spaced 2-4-hour intervals. Results revealed diverse, yet consistent, profiles of IFITM3 localization throughout the gastrula. Within the putative PGC trajectory and surrounding posterior tissues, IFITM3 localized as a large cytoplasmic spot with or without staining in the plasma membrane. IFITM3, like STELLA, was also found in the ventral ectodermal ridge (VER), a posterior progenitor pool that builds the tailbud. The large cytoplasmic spot with plasma membrane staining was exclusive to the posterior region; the visceral yolk sac, non-posterior tissues, and epithelial tissues exhibited spots of IFITM3 without cell surface staining. Co-localization of the intracellular IFITM3 spot with the endoplasmic reticulum, Golgi apparatus or endolysosomes was not observed. That relatively high levels of IFITM3 were found throughout the posterior primitive streak and its derivatives is consistent with evidence that IFITM3, like STELLA, is part of a larger stem/progenitor cell pool at the posterior end of the primitive streak that forms the base of the allantois and builds the fetal-umbilical connection, thus further obfuscating practical phenotypic distinctions between so-called PGCs and surrounding soma.

Background PRDM1 is a transcriptional repressor that contributes to primordial germ cell (PGC) development. During early gastrulation, epiblast-derived PRDM1 is thought to be restricted to a lineage-segregated germ line in the allantois. However, given recent findings that PGCs overlap an allantoic progenitor pool that contributes widely to the fetal-umbilical interface, posterior PRDM1 may also contribute to soma. Results Within the posterior mouse gastrula (Early Streak – 12-s stages, ~E6.75–9.0), PRDM1 localized to all tissues containing putative PGCs; however, PRDM1 was also found in all three primary germ layers, their derivatives, and two presumptive growth centers, the Allantoic Core Domain and Ventral Ectodermal Ridge. While PRDM1 and STELLA colocalized predominantly within the hindgut, where putative PGCs reside, other colocalizing cells were found in non-PGC sites. Additional PRDM1 and STELLA cells were found independent of each other throughout the posterior region, including the hindgut. The Prdm1-Cre-driven reporter supported PRDM1 localization in the majority of sites; however, some Prdm1 descendants were found in sites independent of PRDM1 protein, including allantoic mesothelium and hindgut endoderm. Conclusion Posterior PRDM1 contributes more broadly to the developing fetal-maternal connection than previously recognized, and PRDM1 and STELLA, while overlapping in putative PGCs, also co-localize in several other tissues.

All sequencing data are available from NCBI GEO https://www.ncbi.nlm. nih.gov/geo under accession number GSE139005 and NCBI SRA (https://www.ncbi.nlm.nih.gov/sra) under accession number SRP226023. The RNAseq data used in this research is from the following accession numbers: the mouse data from E9.5 to E18.5 in female and male sorted Oct4-EGFP gonads used for Figs 1, 2, 4, 5, and 10 was obtained through ArrayExpress: E-MTAB-4616; the human data comparing female germ cells versus somatic cells used for Fig 3A was obtained through sperm. Here, we analyzed data from public repositories and isolated these developing cells to examine their gene expression patterns throughout embryonic development. Together these data suggest that the dynamic expression of Taf4b and other TFIID family members are dependent on the well-established reproductive cell regulators Dazl and Stra8. This understanding of Taf4b gene expression and regulation in mouse reproductive cell development is likely conserved during development of human cells and offers novel insights into the interconnectedness of the factors that govern the formation of healthy eggs and sperm.