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Mechanisms of Human Embryo Development: from Cell Fate to Tissue Shape and Back Marta N © 2020. Published by The Company of Biologists Ltd | Development (2020) 147, dev190629. doi:10.1242/dev.190629 REVIEW Mechanisms of human embryo development: from cell fate to tissue shape and back Marta N. Shahbazi* ABSTRACT activated ion channels (Coste et al., 2010), mechanosensitive Gene regulatory networks and tissue morphogenetic events drive the transcription factors (Dupont et al., 2011) or directly by the nucleus emergence of shape and function: the pillars of embryo development. (Kirby and Lammerding, 2018). Once sensed, mechanical cues – Although model systems offer a window into the molecular biology of are transduced into biochemical signals a process known as cell fate and tissue shape, mechanistic studies of our own mechanotransduction (Chan et al., 2017). The conversion of development have so far been technically and ethically challenging. mechanical cues into biochemical signals leads to changes in However, recent technical developments provide the tools to gene expression and protein activity that control cell behaviour, cell describe, manipulate and mimic human embryos in a dish, thus fate specification and tissue patterning. opening a new avenue to exploring human development. Here, I Current consensus focuses on two main ideas to explain the discuss the evidence that supports a role for the crosstalk between emergence of tissue patterns in response to morphogen (see Glossary, ‘ ’ cell fate and tissue shape during early human embryogenesis. This is Box1)signals.Inthe positional information model (Wolpert, a critical developmental period, when the body plan is laid out and 1969), the concentration of a morphogen serves as a coordinate of the many pregnancies fail. Dissecting the basic mechanisms that position of a cell within a tissue. Cells respond to a specific coordinate cell fate and tissue shape will generate an integrated morphogen concentration making a specific fate choice. Therefore, understanding of early embryogenesis and new strategies for an existing asymmetry is transformed into a pattern of cell fates. On therapeutic intervention in early pregnancy loss. the contrary, in the reaction-diffusion model (Turing, 1952), pattern formation is a self-organising phenomenon. The basic idea behind KEY WORDS: Human embryo, Morphogenesis, Cell fate, Embryonic this model is the presence of a short-range activator that induces its stem cells, Aneuploidy, Polarisation own expression and the expression of a long-range inhibitor. A spontaneous increase in the local concentration of the activator (a Introduction symmetry-breaking event) will induce a further increase in the levels Developmental biologists are faced with a question of form and of the activator and expression of the inhibitor. However, as the function. Starting from a relatively simple spore, seed or egg, inhibitor has a higher diffusion rate, this will lead to a peak of multiple cell types arise that perform specific functions. These activation surrounded by a valley of repression. These two different cells organise into diverse configurations, leading to the mechanisms, positional information and reaction-diffusion, co-exist emergence of tissues of a defined form. Development requires during development to generate patterns (Green and Sharpe, 2015). mechanical changes in cell and tissue shape, which drive The use of model organisms allows us to explore the mechanisms morphogenesis, and gene expression changes, which regulate cell that orchestrate the crosstalk between cell fate and tissue shape. For fate decisions and tissue patterning. These two developmental example, cytoskeletal forces lead to the acquisition of cell polarity processes are not independent, as changes in cell fate can modify the and the differential segregation of cell fate determinants in architecture of tissues, and vice versa (Chan et al., 2017). C. elegans (Goehring et al., 2011), an emerging lumen traps Mechanochemical feedback at the molecular, cellular and tissue fibroblast growth factor (FGF) molecules, which lead to levels coordinates this crosstalk and instructs tissue self-organisation differentiation in the lateral line primordium of zebrafish (Durdu (see Glossary, Box 1) (Hannezo and Heisenberg, 2019). et al., 2014), and tissue deformations control midgut differentiation Molecular motors generate mechanical forces that are transmitted in Drosophila embryos (Desprat et al., 2008). As human beings, our across tissues via the cytoskeleton and cell-cell adhesion proteins own development remains the most significant to study, yet is still (Heisenberg and Bellaiche, 2013). In the embryo, this leads to mysterious due to technical and ethical limitations (Box 2). In this changes in cell shape and position, to large tissue-scale Review, I draw upon knowledge gained from studies in model deformations, and consequently to morphogenesis. Cells sense organisms, embryonic stem cell research and human embryology to mechanical cues – a process termed mechanosensation – via propose mechanistic models of three critical developmental events: extracellular matrix (ECM) adhesion proteins (Schwartz, 2010), compaction and polarisation at the cleavage stage; embryonic cell-cell adhesion proteins (Benham-Pyle et al., 2015), stretch- epithelialisation at the time of implantation; and pluripotent cell differentiation at gastrulation (Fig. 1). The emerging picture supports a role for the crosstalk between tissue shape and cell fate MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge as a determinant of human embryogenesis. Biomedical Campus, Cambridge CB2 0QH, UK. *Author for correspondence ([email protected]) Compaction and polarisation: the first morphogenetic transformation M.N.S., 0000-0002-1599-5747 Compaction This is an Open Access article distributed under the terms of the Creative Commons Attribution At the 8- to 16-cell stage, human embryos undergo the process of License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. compaction; blastomeres (see Glossary, Box 1) adhere tightly to DEVELOPMENT 1 REVIEW Development (2020) 147, dev190629. doi:10.1242/dev.190629 Box 1. Glossary Box 2. Historical perspective of human embryo Amnion. An extra-embryonic membrane that protects the development developing foetus from mechanical damage and the maternal The birth of human embryology as a scientific discipline is intimately immune response. linked to the creation of human embryo collections (Yamada et al., 2015; Amniotes. A clade of vertebrates in which the embryo develops while Gasser et al., 2014). The pioneering work of Franklin Mall led to the being protected by extra-embryonic membranes, including the amnion. It creation of the Carnegie collection in 1887, which harbours more than encompasses reptiles, birds and mammals. 10,000 human embryo specimens, and established the basic staging Amniotic cavity. Fluid-filled sac located between the amnion and the criteria for the developmental classification of human embryos (Keibel embryo, the function of which is to protect the embryo from mechanical and Mall, 1912). Other collections were later created, such as the Kyoto damage and the maternal immune system. collection, which today holds ∼44,000 specimens (Nishimura et al., Blastocoel. Fluid-filled cavity present in blastocyst stage embryos. 1968). Much of our current textbook knowledge of human development is Blastocyst. An embryo composed of an outer trophectoderm layer, an derived from the early descriptive studies of these samples. inner cell mass and an internal blastocoel cavity. The development of in vitro fertilisation (IVF) of human eggs initiated a Blastomeres. Cells of the early embryo, formed by cleavage of the revolution in human embryo and stem cell research and human zygote. reproduction (Edwards et al., 1969; Rock and Menkin, 1944; Shettles, Cytotrophoblast. Trophectoderm stem cell compartment of the human 1955). This initial milestone was followed by the development of embryo. It plays a key role during blastocyst implantation and it generates conditions to culture fertilised human eggs in vitro for up to 5-6 days differentiated trophectoderm cells such as syncytiotrophoblast and (Edwards et al., 1970; Steptoe et al., 1971), and ultimately led to the birth extravillous trophoblast. of the first IVF baby in 1978, thanks to the tireless efforts of Robert Ectoderm. Outermost primary germ layer that gives rise to the nervous Edwards, Patrick Steptoe and Jean Purdy. Since then, the field of human system, the epidermis and its appendages. embryology has flourished. IVF has allowed scientists to describe the Embryonic genome activation. The process whereby zygotic dynamics of key morphogenetic processes during early human transcription is initiated and takes over the maternally stored mRNAs development, such as cleavage, compaction and blastulation (Wong and proteins. In human embryos, it takes place at the four- to eight-cell et al., 2010; Marcos et al., 2015; Iwata et al., 2014); to characterise cell stage transition. lineage specification events by studying the transcriptional and Embryoid body. Three dimensional aggregates of pluripotent stem cells epigenetic profiles of all the cells present in a developing human commonly used to study differentiation. embryo (Niakan and Eggan, 2013; Petropoulos et al., 2016; Braude Endoderm. Innermost primary germ layer that gives rise to the et al., 1988; Zhu et al., 2018); to identify
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