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The rostrocaudal (head-to-tail) axis is supplied by populations of progenitors at the caudal end of the embryo. Despite recent advances characterising one of these populations, the neuromesodermal progenitors, their nature and relationship to other populations remains unclear. Here we show that neuromesodermal progenitors are a single Sox2lowTlow entity whose choice of neural or mesodermal fate is dictated by their position in the progenitor region. The choice of mesoderm fate is Wnt/β-catenin dependent. Wnt/β-catenin signalling is also required for a previously unrecognised phase of progenitor expansion during mid-trunk formation. Lateral/ventral mesoderm progenitors represent a distinct committed state that is unable to differentiate to neural fates, even upon overexpression of the neural transcription factor Sox2. They do not require Wnt/β-catenin signalling for mesoderm differentiation. This information aids the correct interpretation of in vivo genetic studies and the development of in vitro protocols for generating physiologically-relevant cell populations of clinical interest. Our bodies, like those of all animals with a backbone, form during embryo development in a head-to-tail sequence. This process is fuelled by populations of proliferating cells called progenitor cells, which are found in an early embryonic structure called the primitive streak, and later at the tail-end of the embryo. One of these populations – known as the neuromesodermal progenitors (or NMPs) – produces the animal’s spinal cord, muscle and bone tissue. However, it is not clear how this cell population is maintained or what triggers these cells to specialise into the correct cell type. It is even unclear whether NMPs are a single cell type or a collection of several types of progenitor, each with a slightly different propensity to make spinal cord or muscle and bone. Answering these questions could inform the future development of cell-replacement therapies for conditions such as spinal injuries. Wymeersch et al. used a range of techniques to identify, map the fate, and assess the developmental potential of progenitors in the primitive streak. This revealed fine-grained differences in the fates adopted by cells in the progenitor region. However, these regional differences were found to result from the progenitor cells’ extensive ability to respond to signals they receive from their environment, rather than being hard-wired into the progenitor cells. In fact, Wymeersch et al. detected only two distinct cell types: the NMPs and a new cell population termed lateral/paraxial mesoderm progenitors (or LPMPs), which, unlike NMPs, do not form nerve cells. Further experiments investigated the molecular signals present in the environment of these progenitors that help to decide their fate. NMPs respond to an important developmental signal, called Wnt, by adopting a so-called mesoderm fate. This signal also induces NMPs to undergo a previously unknown phase of proliferation during the formation of the animal’s body. LPMPs, on the other hand, do not require Wnt to form mesoderm. These findings show that studies with embryos can identify new progenitor populations that might be clinically relevant, and reveal new ways in which a cell’s environment inside an embryo can determine its fate.

Early mouse development is regulated and accompanied by dynamic changes in chromatin modifications, including G9a-mediated histone H3 lysine 9 dimethylation (H3K9me2). Previously, we provided insights into its role in post-implantation development (Zylicz et al., 2015). Here we explore the impact of depleting the maternally inherited G9a in oocytes on development shortly after fertilisation. We show that G9a accumulates typically at 4 to 8 cell stage to promote timely repression of a subset of 4 cell stage-specific genes. Loss of maternal inheritance of G9a disrupts the gene regulatory network resulting in developmental delay and destabilisation of inner cell mass lineages by the late blastocyst stage. Our results indicate a vital role of this maternally inherited epigenetic regulator in creating conducive conditions for developmental progression and on cell fate choices.

Deletion of Sox2 from mouse embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here, we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from naïve pluripotency.

Human germline–soma segregation occurs during weeks 2–3 in gastrulating embryos. Although direct studies are hindered, here, we investigate the dynamics of human primordial germ cell (PGCs) specification using in vitro models with temporally resolved single-cell transcriptomics and in-depth characterisation using in vivo datasets from human and nonhuman primates, including a 3D marmoset reference atlas. We elucidate the molecular signature for the transient gain of competence for germ cell fate during peri-implantation epiblast development. Furthermore, we show that both the PGCs and amnion arise from transcriptionally similar TFAP2A-positive progenitors at the posterior end of the embryo. Notably, genetic loss of function experiments shows that TFAP2A is crucial for initiating the PGC fate without detectably affecting the amnion and is subsequently replaced by TFAP2C as an essential component of the genetic network for PGC fate. Accordingly, amniotic cells continue to emerge from the progenitors in the posterior epiblast, but importantly, this is also a source of nascent PGCs.

Deletion of Sox2 from embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from na ve pluripotency.

A Bayesian method is proposed for estimating an inverse covariance matrix from Gaussian data. The method is based on a prior that allows the off‐diagonal elements of the inverse covariance matrix to be zero, and in many applications results in a parsimonious parameterisation of the covariance matrix. No assumption is made about the structure of the corresponding graphical model, so the method applies to both nondecomposable and decomposable graphs. All the parameters are estimated by model averaging using an efficient Metropolis–Hastings sampling scheme. A simulation study demonstrates that the method produces statistically efficient estimators of the covariance matrix, when the inverse covariance matrix is sparse. The methodology is illustrated by applying it to three examples that are high‐dimensional relative to the sample size.