Explore the vast range of titles available.

Somitogenesis, the segmentation of the antero-posterior axis in vertebrates, is thought to result from the interactions between a genetic oscillator and a posterior-moving determination wavefront. The segment (somite) size is set by the product of the oscillator period and the velocity of the determination wavefront. Surprisingly, while the segmentation period can vary by a factor three between 20 °C and 32 °C, the somite size is constant. How this temperature independence is achieved is a mystery that we address in this study. Using RT-qPCR we show that the endogenous fgf8 mRNA concentration decreases during somitogenesis and correlates with the exponent of the shrinking pre-somitic mesoderm (PSM) size. As the temperature decreases, the dynamics of fgf8 and many other gene transcripts, as well as the segmentation frequency and the PSM shortening and tail growth rates slows down as T–T c (with T c  = 14.4 °C). This behavior characteristic of a system near a critical point may account for the temperature independence of somitogenesis in zebrafish. In Zebrafish, the dynamics of fgf8 and other gene transcripts as well as segmentation frequency, shortening of pre-somitic mesoderm and tail growth rate slows down with lower temperature. This may explain the temperature independence of somitogenesis.

Histone methylation can occur at various sites in histone proteins, primarily on lysine and arginine residues, and it can be governed by multiple positive and negative regulators, even at a single site, to either activate or repress transcription. It is now apparent that histone methylation is critical for almost all stages of development, and its proper regulation is essential for ensuring the coordinated expression of gene networks that govern pluripotency, body patterning and differentiation along appropriate lineages and organogenesis. Notably, developmental histone methylation is highly dynamic. Early embryonic systems display unique histone methylation patterns, prominently including the presence of bivalent (both gene-activating and gene-repressive) marks at lineage-specific genes that resolve to monovalent marks during differentiation, which ensures that appropriate genes are expressed in each tissue type. Studies of the effects of methylation on embryonic stem cell pluripotency and differentiation have helped to elucidate the developmental roles of histone methylation. It has been revealed that methylation and demethylation of both activating and repressive marks are essential for establishing embryonic and extra-embryonic lineages, for ensuring gene dosage compensation via genomic imprinting and for establishing body patterning via HOX gene regulation. Not surprisingly, aberrant methylation during embryogenesis can lead to defects in body patterning and in the development of specific organs. Human genetic disorders arising from mutations in histone methylation regulators have revealed their important roles in the developing skeletal and nervous systems, and they highlight the overlapping and unique roles of different patterns of methylation in ensuring proper development.

Human embryogenesis is hallmarked by two phases of yolk sac development. The primate hypoblast gives rise to a transient primary yolk sac, which is rapidly superseded by a secondary yolk sac during gastrulation. Moreover, primate embryos form extraembryonic mesoderm prior to gastrulation, in contrast to mouse. The function of the primary yolk sac and the origin of extraembryonic mesoderm remain unclear. Here, we hypothesise that the hypoblast-derived primary yolk sac serves as a source for early extraembryonic mesoderm, which is supplemented with mesoderm from the gastrulating embryo. We discuss the intricate relationship between the yolk sac and the primate embryo and highlight the pivotal role of the yolk sac as a multifunctional hub for haematopoiesis, germ cell development and nutritional supply. Why do human embryos need a yolk sac and how does it form? This Perspective by Thorsten Boroviak and Connor Ross explores the development and function of the yolk sac in primate embryogenesis.

Tracking the progeny of single cells is necessary for building lineage trees that recapitulate processes such as embryonic development and stem cell differentiation. In classical lineage tracing experiments, cells are fluorescently labelled to allow identification by microscopy of a limited number of cell clones. To track a larger number of clones in complex tissues, fluorescent proteins are now replaced by heritable DNA barcodes that are read using next-generation sequencing. In prospective lineage tracing, unique DNA barcodes are introduced into single cells through genetic manipulation (using, for example, Cre-mediated recombination or CRISPR–Cas9-mediated editing) and tracked over time. Alternatively, in retrospective lineage tracing, naturally occurring somatic mutations can be used as endogenous DNA barcodes. Finally, single-cell mRNA-sequencing datasets that capture different cell states within a developmental or differentiation trajectory can be used to recapitulate lineages. In this Review, we discuss methods for prospective or retrospective lineage tracing and demonstrate how trajectory reconstruction algorithms can be applied to single-cell mRNA-sequencing datasets to infer developmental or differentiation tracks. We discuss how these approaches are used to understand cell fate during embryogenesis, cell differentiation and tissue regeneration.

Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.

Gender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment.

From embryonic development, postnatal growth and adult homeostasis to reparative and disease states, cells and tissues undergo constant changes in genome activity, cell fate, proliferation, movement, metabolism and growth. Importantly, these biological state transitions are coupled to changes in the mechanical and material properties of cells and tissues, termed mechanical state transitions. These mechanical states share features with physical states of matter, liquids and solids. Tissues can switch between mechanical states by changing behavioural dynamics or connectivity between cells. Conversely, these changes in tissue mechanical properties are known to control cell and tissue function, most importantly the ability of cells to move or tissues to deform. Thus, tissue mechanical state transitions are implicated in transmitting information across biological length and time scales, especially during processes of early development, wound healing and diseases such as cancer. This Review will focus on the biological basis of tissue-scale mechanical state transitions, how they emerge from molecular and cellular interactions, and their roles in organismal development, homeostasis, regeneration and disease.Tissues undergo changes in their mechanical and material properties through alterations in cytoskeleton organization, extracellular matrix adhesion and cell–cell connectivity. These mechanical state transitions orchestrate cell proliferation and movement and tissue growth during development, in adult tissue repair and in disease contexts.

Key Points In response to myocardial infarction, damaged adult cardiomyocytes are replaced by activated fibroblasts that form a fibrotic scar, leading to reduced cardiac function and heart failure. As the adult heart has limited regenerative capacity, there is a need to develop innovative strategies to enhance cardiac repair and regeneration. Cellular replacement strategies for heart repair, in which stem cells and other cell types are injected directly into the injured heart or into the coronary circulation, have shown modest beneficial effects on cardiac function. An alternative approach is to reprogramme non-muscle cells in the injured heart to adopt a cardiac fate. Positive cell cycle regulators are highly expressed in the embryonic heart and downregulated in the adult heart. Activation of various signalling pathways in the heart can modestly reactivate proliferation in adult cardiomyocytes. Identification of transcription factors and microRNAs that control heart formation has enabled reprogramming of non-muscle cells into cardiomyocytes and other cell types of the heart. Following injury, in vivo reprogramming of non-myocytes into cardiomyocytes has improved heart function in mice. Epicardial cells are activated following cardiac injury and have the potential to differentiate into various cell types, offering a niche that can be targeted with small molecules. This provides an attractive approach for regenerative medicine. The inflammatory response has a role in cardiac repair following injury. Several studies have shed light on both positive and negative roles of the inflammatory response in tissue repair and regeneration. The adult mammalian heart has limited potential for regeneration and repair. Progress has been made in elucidating the cellular processes and regulatory mechanisms involved in heart growth and development, and this can be exploited to restore function in the injured adult heart. As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and death. The cellular processes and regulatory mechanisms involved in heart growth and development can be exploited to repair the injured adult heart through 'reawakening' pathways that are active during embryogenesis. Heart function has been restored in rodents by reprogramming non-myocytes into cardiomyocytes, by expressing transcription factors (GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs (miR-1, miR-133, miR-208 and miR-499) that control cardiomyocyte identity. Stimulating cardiomyocyte dedifferentiation and proliferation by activating mitotic signalling pathways involved in embryonic heart growth represents a complementary approach for heart regeneration and repair. Recent advances in understanding the mechanistic basis of heart development offer exciting opportunities for effective therapies for heart failure.

In mice, transcription initiates at the mid-one-cell stage and transcriptional activity dramatically increases during the two-cell stage, a process called zygotic gene activation (ZGA). Associated with ZGA is a marked change in the pattern of gene expression that occurs after the second round of DNA replication. To distinguish ZGA before and after the second-round DNA replication, the former and latter are called minor and major ZGA, respectively. Although major ZGA are required for development beyond the two-cell stage, the function of minor ZGA is not well understood. Transiently inhibiting minor ZGA with 5, 6-dichloro-1-β-D-ribofuranosyl-benzimidazole (DRB) resulted in the majority of embryos arresting at the two-cell stage and retention of the H3K4me3 mark that normally decreases. After release from DRB, at which time major ZGA normally occurred, transcription initiated with characteristics of minor ZGA but not major ZGA, although degradation of maternal mRNA normally occurred. Thus, ZGA occurs sequentially starting with minor ZGA that is critical for the maternal-to-zygotic transition.