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Key Points During development, cells become progressively restricted in their lineage choices. The allocation of cells to a specific lineage is regulated by the activities of key signalling pathways and developmentally regulated transcription factors. The first binary cell lineage decision, between the trophectoderm (TE) and the inner cell mass (ICM), is governed by the exclusive expression of caudal-type homeobox protein 2 (CDX2) and octamere-binding transcription factor 3/4 (OCT3/4; also known as POU5F1) in TE or ICM, respectively. The ICM is further subdivided into the primitive endoderm and epiblast by expression of GATA-binding factor 6 (GATA6) and nanog. Signals from the extraembryonic tissues, namely the TE and primitive endoderm, have instructive roles in setting up the embryonic axes and are the source of growth factors and their antagonists that regulate cell type specification in epiblast derivatives during gastrulation. The primitive streak is the site where the mesoderm and definitive endoderm are formed and it is induced in response to Wnt and transforming growth factor β (TGFβ)–nodal signalling. At the primitive streak, cells are allocated to specific fates according to their spatio-temporal position in the streak. The positional information reflects differences in signalling strength of fibroblast growth factor 8 (FGF8), WNT3 or WNT3A and nodal–SMAD2 and SMAD3 and bone morphogenetic protein 4 (BMP4), which are integrated to direct cell lineage specification and regulate morphogenesis. Segregation of primordial germ cells (PGCs) from the somatic lineages at gastrulation requires BMP4–SMAD1 and SMAD5 signals from the extraembryonic ectoderm. Primordial germ cells undergo extensive epigenetic reprogramming to maintain pluripotency throughout the life cycle. Genetic studies combined with in vivo imaging analysis have identified signalling pathways and developmentally regulated transcription factors that govern cell lineage allocation and axis patterning in the early mammalian embryo. These mechanisms are also conserved in lower vertebrates. Genetic studies have identified the key signalling pathways and developmentally regulated transcription factors that govern cell lineage allocation and axis patterning in the early mammalian embryo. Recent advances have uncovered details of the molecular circuits that tightly control cell growth and differentiation in the mammalian embryo from the blastocyst stage, through the establishment of initial anterior–posterior polarity, to gastrulation, when the germ cells are set aside and the three primary germ layers are specified. Relevant studies in lower vertebrates indicate the conservation and divergence of regulatory mechanisms for cell lineage allocation and axis patterning.

The T-box transcription factor (TF) Eomesodermin/Tbr2 (Eomes) is essential for maintenance of the trophectoderm (TE) lineage, but the molecular mechanisms underlying this critical role remain obscure. Here, we show in trophoblast stem cells (TSCs) that Eomes partners with several TE-specific TFs as well as chromatin remodellers, including Brg1 and other subunits of the BAF complex. Degron-mediated Eomes protein depletion results in genome-wide loss of chromatin accessibility at TSC-specific loci. These overlap with a subset of sites that lose accessibility following Brg1 inhibition, suggesting that Eomes acts as a “doorstop” controlling TSC chromatin accessibility. Eomes depletion also causes transcriptional misregulation of TSC maintenance and early differentiation markers. An additional subset of Eomes-dependent genes encode intercellular/matricellular interaction and cytoskeletal components, likely explaining the implantation defects of Eomes-null embryos. Thus, Eomes promotes TE lineage maintenance by sustaining trophectoderm-specific chromatin accessibility, while promoting the gene regulatory networks that modulate expansion and cell behaviour during implantation. Eomes is a critical transcription factor in trophectoderm development. Here, the authors uncovered the molecular basis of Eomes function in embryo implantation and expansion of this extra-embryonic lineage.

Growth and survival of the mammalian embryo within the uterine environment depends on the placenta, a highly complex vascularized organ comprised of both maternal and foetal tissues. Recent experiments demonstrate that the zinc finger transcriptional repressor Prdm1 /Blimp1 is essential for specification of spiral artery trophoblast giant cells (SpA-TGCs) that invade and remodel maternal blood vessels. To learn more about functional contributions made by Blimp1+ cell lineages here we perform the first single-cell RNA-seq analysis of the placenta. Cell types of both foetal and maternal origin are profiled. Comparisons with microarray datasets from mutant placenta and in vitro differentiated trophoblast stem cells allow us to identify Blimp1-dependent transcripts enriched in SpA-TGCs. Our experiments provide new insights into the functionally distinct cell types present at the maternal–foetal interface and advance our knowledge of dynamic gene expression patterns controlling placental morphogenesis and vascular mimicry. The zinc finger transcriptional repressor Prdm1 /Blimp1 is essential for remodelling maternal blood vessels in a subset of trophoblast cells. Here, the authors perform single-cell RNA-seq analysis on this Blimp1+ lineage, identifying functionally distinct cell types present at the maternal–foetal interface.

The zinc finger transcription factor Blimp1/PRDM1 regulates gene expression in diverse cell types. Its activity controls the maternal decidual response at early post-implantation stages of development. The present experiments demonstrate surprisingly that Blimp1 activity in the uterus is required for tissue remodelling at sites of embryonic failure. Moreover Blimp1 mutant females are refractory to RU486 induced decidual shedding. RNA-seq together with immunostaining experiments strongly suggest that the failure to up-regulate expression of the matrix metalloprotease Mmp10 in combination with insufficient suppression of BMP signalling, likely explain Blimp1-dependent phenotypic changes. In the post-partum uterus Blimp1 together with Mmp10 are highly upregulated at sites of tissue repair following placental detachment. Conditional Blimp1 removal significantly impairs the re-epithelization process and severely impacts involution of the endometrium and luminal epithelium. Overall these results identify Blimp1 as a master regulator of uterine tissue remodelling and repair. The uterus undergoes successive rounds of pregnancy associated tissue remodelling. Here they show that Blimp1/PRDM1 activity is required in the uterine stroma during both gestational and post-partum uterine repair in the mouse.

The essential roles played by Nodal and Bmp signalling during early mouse development have been extensively documented. Here we use conditional deletion strategies to investigate functional contributions made by Nodal, Bmp and Smad downstream effectors during primordial germ cell (PGC) development. We demonstrate that Nodal and its target gene Eomes provide early instructions during formation of the PGC lineage. We discover that Smad2 inactivation in the visceral endoderm results in increased numbers of PGCs due to an expansion of the PGC niche. Smad1 is required for specification, whereas in contrast Smad4 controls the maintenance and migration of PGCs. Additionally we find that beside Blimp1, down-regulated phospho-Smad159 levels also distinguishes PGCs from their somatic neighbours so that emerging PGCs become refractory to Bmp signalling that otherwise promotes mesodermal development in the posterior epiblast. Thus balanced Nodal/Bmp signalling cues regulate germ cell versus somatic cell fate decisions in the early posterior epiblast. How Nodal and Bmp pathways interact during primordial germ cell (PGC) formation remains unclear. Here, the authors show Nodal signalling via Eomes in the epiblast, together with Smad2 in the visceral endoderm, regulates formation of the mouse PGC lineage, while Smad1 specifies PGCs and Smad4 controls PGC migration.

Female mammals produce milk to feed their newborn offspring before teeth develop and permit the consumption of solid food. Intestinal enterocytes dramatically alter their biochemical signature during the suckling-to-weaning transition. The transcriptional repressor Blimp1 is strongly expressed in immature enterocytes in utero, but these are gradually replaced by Blimp1⁻ crypt-derived adult enterocytes. Here we used a conditional inactivation strategy to eliminate Blimp1 function in the developing intestinal epithelium. There was no noticeable effect on gross morphology or formation of mature cell types before birth. However, survival of mutant neonates was severely compromised. Transcriptional profiling experiments reveal global changes in gene expression patterns. Key components of the adult enterocyte biochemical signature were substantially and prematurely activated. In contrast, those required for processing maternal milk were markedly reduced. Thus, we conclude Blimp1 governs the developmental switch responsible for postnatal intestinal maturation.

The hierarchical relationships between various stem and progenitor cell subpopulations driving mammary gland morphogenesis and homoeostasis are poorly understood. Conditional inactivation experiments previously demonstrated that expression of the zinc finger transcriptional repressor Blimp1/PRDM1 is essential for the establishment of epithelial cell polarity and functional maturation of alveolar cells. Here we exploit a Prdm1.CreERT2-LacZ reporter allele for lineage tracing experiments. Blimp1 expression marks a rare subpopulation of unipotent luminal stem cells that initially appear in the embryonic mammary gland at around E17.5 coincident with the segregation of the luminal and basal compartments. Fate mapping at multiple time points in combination with whole-mount confocal imaging revealed these long-lived unipotent luminal stem cells survive consecutive involutions and retain their identity throughout adult life. Blimp1 + luminal stem cells give rise to Blimp1 − progeny that are invariably Elf5 + ERα − PR − . Thus, Blimp1 expression defines a mammary stem cell subpopulation with unique functional characteristics. The role of stem/progenitor cell populations in mammary gland morphogenesis is not well understood. Here, the authors show that a transcriptional repressor, Blimp1, is expressed in a rare luminal stem cell population, which contribute to duct formation, and survive multiple rounds of pregnancy and involution.

The transcriptional repressor Blimp1 controls cell fate decisions in the developing embryo and adult tissues. Here we describe Blimp1 expression and functional requirements within maternal uterine tissues during pregnancy. Expression is robustly up-regulated at early post-implantation stages in the primary decidual zone (PDZ) surrounding the embryo. Conditional inactivation results in defective formation of the PDZ barrier and abnormal trophectoderm invasion. RNA-Seq analysis demonstrates down-regulated expression of genes involved in cell adhesion and markers of decidualisation. In contrast, genes controlling immune responses including IFNγ are up-regulated. ChIP-Seq experiments identify candidate targets unique to the decidua as well as those shared across diverse cell types including a highly conserved peak at the Csf-1 gene promoter. Interestingly Blimp1 inactivation results in up-regulated Csf1 expression and macrophage recruitment into maternal decidual tissues. These results identify Blimp1 as a critical regulator of tissue remodelling and maternal tolerance during early stages of pregnancy. The transcriptional repressor Blimp1/PRDM1 regulates cell fate decisions in the developing embryo and adult tissues. Here the authors show that conditional inactivation within maternal uterine tissues results in a defective primary decidual zone barrier, increased expression of inflammatory cytokines IFN gamma and Csf1, and early embryonic lethality during pregnancy.

The neonatal intestine is a very complex and dynamic organ that must rapidly adapt and remodel in response to a barrage of environmental stimuli during the first few postnatal weeks. Recent studies demonstrate that the zinc finger transcriptional repressor Blimp1/Prdm1 plays an essential role governing postnatal reprogramming of intestinal enterocytes during this period. Functional loss results in global changes in gene expression patterns, particularly in genes associated with metabolic function. Here we engineered a knock-in allele expressing an eGFP-tagged fusion protein under control of the endogenous regulatory elements and performed genome wide ChIP-seq analysis to identify direct Blimp1 targets and further elucidate the function of Blimp1 in intestinal development. Comparison with published human and mouse datasets revealed a highly conserved core set of genes including interferon-inducible promoters. Here we show that the interferon-inducible transcriptional activator Irf1 is constitutively expressed throughout fetal and postnatal intestinal epithelium development. ChIP-seq demonstrates closely overlapping Blimp1 and Irf1 peaks at key components of the MHC class I pathway in fetal enterocytes. The onset of MHC class I expression coincides with down-regulated Blimp1 expression during the suckling to weaning transition. Collectively, these experiments strongly suggest that in addition to regulating the enterocyte metabolic switch, Blimp1 functions as a gatekeeper in opposition to Irf1 to prevent premature activation of the MHC class I pathway in villus epithelium to maintain tolerance in the neonatal intestine.

Trophoblast stem cells (TSCs) give rise to specialized cell types within the placenta. However, the regulatory mechanisms that guide trophoblast cell fate decisions during placenta development remain ill defined. Here we exploited ATAC-seq and transcriptional profiling strategies to describe dynamic changes in gene expression and chromatin accessibility during TSC differentiation. We detect significantly increased chromatin accessibility at key genes upregulated as TSCs exit from the stem cell state. However, downregulated gene expression is not simply due to the loss of chromatin accessibility in proximal regions. Additionally, transcriptional targets recognized by the zinc finger transcriptional repressor Prdm1 /Blimp1, an essential regulator of placenta development, were identified in ChIP-seq experiments. Comparisons with previously reported ChIP-seq datasets for primordial germ cell-like cells and E18.5 small intestine, combined with functional annotation analysis revealed that Blimp1 has broadly shared as well as cell type-specific functional activities unique to the trophoblast lineage. Importantly, Blimp1 not only silences TSC gene expression but also prevents aberrant activation of divergent developmental programmes. Overall the present study provides new insights into the chromatin landscape and Blimp1-dependent regulatory networks governing trophoblast gene expression.