Oscillatory control of embryonic development.

Proper embryonic development depends on the timely progression of a genetic program. One of the key mechanisms for achieving precise control of developmental timing is to use gene expression oscillations. In this Review, we examine how gene expression oscillations encode temporal information during vertebrate embryonic development by discussing the gene expression oscillations occurring during somitogenesis, neurogenesis, myogenesis and pancreas development. These oscillations play important but varied physiological functions in different contexts. Oscillations control the period of somite formation during somitogenesis, whereas they regulate the proliferation-to-differentiation switch of stem cells and progenitor cells during neurogenesis, myogenesis and pancreas development. We describe the similarities and differences of the expression pattern in space (i.e. whether oscillations are synchronous or asynchronous across neighboring cells) and in time (i.e. different time scales) of mammalian Hes/zebrafish Her genes and their targets in different tissues. We further summarize experimental evidence for the functional role of their oscillations. Finally, we discuss the outstanding questions for future research.

Spatiotemporal control of pattern formation during somitogenesis.

Spatiotemporal patterns widely occur in biological, chemical, and physical systems. Particularly, embryonic development displays a diverse gamut of repetitive patterns established in many tissues and organs. Branching treelike structures in lungs, kidneys, livers, pancreases, and mammary glands as well as digits and bones in appendages, teeth, and palates are just a few examples. A fascinating instance of repetitive patterning is the sequential segmentation of the primary body axis, which is conserved in all vertebrates and many arthropods and annelids. In these species, the body axis elongates at the posterior end of the embryo containing an unsegmented tissue. Meanwhile, segments sequentially bud off from the anterior end of the unsegmented tissue, laying down an exquisite repetitive pattern and creating a segmented body plan. In vertebrates, the paraxial mesoderm is sequentially divided into somites. In this review, we will discuss the most prominent models, the most puzzling experimental data, and outstanding questions in vertebrate somite segmentation.

The Role of Fibroblast Growth Factor Signaling in Somitogenesis.

Fibroblast growth factor (FGF) signaling is conserved from cnidaria to mammals (Ornitz and Itoh, 2022) and it regulates several critical processes such as differentiation, proliferation, apoptosis, cell migration, and embryonic development. One pivotal process FGF signaling controls is the division of vertebrate paraxial mesoderm into repeated segmented units called somites (i.e., somitogenesis). Somite segmentation occurs periodically and sequentially in a head-to-tail manner, and lays down the plan for compartmentalized development of the vertebrate body axis (Gomez et al., 2008). These somites later give rise to vertebrae, tendons, and skeletal muscle. Somite segments form sequentially from the anterior end of the presomitic mesoderm (PSM). The periodicity of somite segmentation is conferred by the segmentation clock, comprising oscillatory expression of Hairy and enhancer-of-split (Her/Hes) genes in the PSM. The positional information for somite boundaries is instructed by the double phosphorylated extracellular signal-regulated kinase (ppERK) gradient, which is the relevant readout of FGF signaling during somitogenesis (Sawada et al., 2001; Delfini et al., 2005; Simsek and Ozbudak, 2018; Simsek et al., 2023). In this review, we summarize the crosstalk between the segmentation clock and FGF/ppERK gradient and discuss how that leads to periodic somite boundary formation. We also draw attention to outstanding questions regarding the interconnected roles of the segmentation clock and ppERK gradient, and close with suggested future directions of study.

Periodic inhibition of Erk activity drives sequential somite segmentation.

Sequential segmentation creates modular body plans of diverse metazoan embryos1-4. Somitogenesis establishes the segmental pattern of the vertebrate body axis. A molecular segmentation clock in the presomitic mesoderm sets the pace of somite formation4. However, how cells are primed to form a segment boundary at a specific location remains unclear. Here we developed precise reporters for the clock and double-phosphorylated Erk (ppErk) gradient in zebrafish. We show that the Her1-Her7 oscillator drives segmental commitment by periodically lowering ppErk, therefore projecting its oscillation onto the ppErk gradient. Pulsatile inhibition of the ppErk gradient can fully substitute for the role of the clock, and kinematic clock waves are dispensable for sequential segmentation. The clock functions upstream of ppErk, which in turn enables neighbouring cells to discretely establish somite boundaries in zebrafish5. Molecularly divergent clocks and morphogen gradients were identified in sequentially segmenting species3,4,6-8. Our findings imply that versatile clocks may establish sequential segmentation in diverse species provided that they inhibit gradients.