Molecular specification of germ layers in vertebrate embryos

Abstract

In order to generate the tissues and organs of a multicellular organism, different cell types have to be generated during embryonic development. The first step in this process of cellular diversification is the formation of the three germ layers: ectoderm, endoderm and mesoderm. The ectoderm gives rise to the nervous system, epidermis and various neural crest-derived tissues, the endoderm goes on to form the gastrointestinal, respiratory and urinary systems as well as many endocrine glands, and the mesoderm will form the notochord, axial skeleton, cartilage, connective tissue, trunk muscles, kidneys and blood. Classic experiments in amphibian embryos revealed the tissue interactions involved in germ layer formation and provided the groundwork for the identification of secreted and intracellular factors involved in this process. We will begin this review by summarising the key findings of those studies. We will then evaluate them in the light of more recent genetic studies that helped clarify which of the previously identified factors are required for germ layer formation in vivo, and to what extent the mechanisms identified in amphibians are conserved across other vertebrate species. Collectively, these studies have started to reveal the gene regulatory network (GRN) underlying vertebrate germ layer specification and we will conclude our review by providing examples how our understanding of this GRN can be employed to differentiate stem cells in a targeted fashion for therapeutic purposes.

WNT and BMP regulate roadblocks toward cardiomyocyte differentiation: lessons learned from embryos inform human stem cell differentiation

“…Furthermore, their findings that hESCs generated mostly neural fates under low-BMP/low-Wnt conditions, are consistent with what we know from studies in vertebrates, particularly in Xenopus laevis and chick embryos, where BMP antagonists (chordin, noggin, follistatin) and Wnt antagonists (sFRPs) are expressed in dorsal most mesoderm [recently reviewed by (27)]. More lateral or ventral mesoderm signatures (e.g., blood, cartilage) were induced in hESCs by high-BMP/high-Wnt conditions, again consistent with mesoderm patterning in early embryos.…”

FGF and canonical Wnt signaling cooperate to induce paraxial mesoderm from tailbud neuromesodermal progenitors through regulation of a two-step epithelial to mesenchymal transition

“…Little is known about the molecular factors governing these intermediate states. During vertebrate mesoderm formation, both Wnt and FGF signaling promote the eventual formation of mesenchymal PM from the epithelial epiblast (Kiecker et al, 2016;Kimelman, 2006). Here we show that although both signals promote the formation of mesenchymal mesoderm from an epithelium, they have differential effects on the transitional or partial EMT state.…”

“…All vertebrate embryos form their bodies in an anterior to posterior progression, and the tailbud NMPs are an essential source of new neural and mesodermal cells that contribute to the posteriorly elongating body axis (Beck, 2015;Henrique et al, 2015;Kimelman, 2016;Kimelman and Martin, 2012;Kondoh and Takemoto, 2012;Martin, 2016). While the molecular mechanisms of mesoderm induction during gastrulation are well studied, much less is known about how mesoderm is induced in NMPs (Kiecker et al, 2016;Kimelman, 2006;Martin, 2016). Investigating this process will provide insight into the plasticity of mesoderm induction programs and strengthen our understanding of how the vertebrate body plan is established.…”

“…The first mesoderm-inducing signal discovered was the fibroblast growth factor (FGF) pathway (Dorey and Amaya, 2010;Kiecker et al, 2016). When overexpressed, FGF signaling is sufficient to induce mesoderm in naïve epiblast cells (Kimelman et al, 1988;Kimelman and Kirschner, 1987;Slack et al, 1987).…”

Fibroblast Differentiation and Models of Human Skin

“…(reviewed in )) e development of the mesoderm has been explained by a three-signal model (germ layer speci cation extensively reviewed in (Kiecker et al, 2016)). Candidate factors for mesodermal speci cation include broblast growth factors (FGF), transforming growth factors beta (TGF-β) (speci cally Activin A, and members of the BMP family), and Wnt/β-catenin signaling (Kiecker et al, 2016).…”