Somitogenesis is the process by which

somite The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryogenesis, embryonic stage of somitogenesis, along the head-to-tail axis in segmentation (biology), segmented animals. ...

s form. Somites are bilaterally paired blocks of paraxial mesoderm that form along the anterior-posterior axis of the developing

embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...

vertebrates Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...

. The somites give rise to

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

cartilage Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

tendon A tendon or sinew is a tough band of fibrous connective tissue, dense fibrous connective tissue that connects skeletal muscle, muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tensi ...

endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...

, and

dermis The dermis or corium is a layer of skin between the epidermis (skin), epidermis (with which it makes up the cutis (anatomy), cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from s ...

Overview

During somitogenesis, somites form from the pre-somitic mesoderm, a region of mesoderm at the posterior of the developing embryo. This tissue undergoes convergent extension as the primitive streak regresses, or as the embryo gastrulates. The

notochord The notochord is an elastic, rod-like structure found in chordates. In vertebrates the notochord is an embryonic structure that disintegrates, as the vertebrae develop, to become the nucleus pulposus in the intervertebral discs of the verteb ...

extends from the base of the head to the tail; with it extend thick bands of paraxial mesoderm. As the primitive streak continues to regress, somites form from the pre-somitic mesoderm by 'budding off' periodically from the anterior end of the pre-somitic mesoderm. The underlying developmental signals controlling this periodic formation are thought to conform to a clock-wavefront model. These immature somites then are compacted into an outer layer (the epithelium) and an inner mass (the

mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood, or bone. The interactions between mesenchyme and epithelium help to form nearly ever ...

). Somites, and the segmented structures such as

vertebrae Each vertebra (: vertebrae) is an irregular bone with a complex structure composed of bone and some hyaline cartilage, that make up the vertebral column or spine, of vertebrates. The proportions of the vertebrae differ according to their spinal ...

that arise from them, are each given an identity by the expression of Hox genes within the developing somite. The cells within each somite are specified based on their location within the somite. In addition, they retain the ability to become any kind of somite-derived structure until relatively late in the process of somitogenesis.

Mechanism

Periodicity

Once the cells of the pre-somitic mesoderm are in place following cell migration during gastrulation, oscillatory expression of multiple 'clock' genes begins in these cells. A difference in oscillator timing between the anterior and posterior of the pre-somitic mesoderm leads to the creation of travelling waves of gene expression, analogous to a ' mexican wave'. These largely cell-autonomous oscillations are thought to be driven by autoinhibition of genes in the Hes/Her family, and are thought to synchronise the differentiation of pre-somitic mesoderm cells into somites. These intracellular oscillations are intrinsically noisy and synchrony is achieved by intercellular Notch signalling. The boundary between somites is thought to be patterned by inhibition of ERK signalling by genes in the Hes/Her family, and thus oscillations in gene expression also control the timing, or rate, of somite formation. Once cells have adopted somite

fate Destiny, sometimes also called fate (), is a predetermined course of events. It may be conceived as a predeterminism, predetermined future, whether in general or of an individual. Fate Although often used interchangeably, the words wiktionary ...

they undergo an epithelial-mesenchymal transition and form a new somite. The position of the somite boundary is thought to be controlled by a

gradient In vector calculus, the gradient of a scalar-valued differentiable function f of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p gives the direction and the rate of fastest increase. The g ...

of FGF or Wnt signalling that moves posteriorly at the rate that the embryo elongates and grows, thus coupling somite size to the size of the embryo. Maintenance of undifferentiated cells in the pre-somitic mesoderm by gastrulation or elongation of the pre-somitic mesoderm allows this process to carry on repeatedly, thus explaining the periodic formation of somites. This mechanism explains why the expression of "clock genes" oscillates with a periodicity equal to the time necessary for one somite to form, for example 30 minutes in zebrafish, 90 minutes in chicks, and 100 minutes in snakes. The identity of clock genes and the mechanism by which they oscillate can vary between different species, for instance zebrafish exhibits a simple

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...

loop, or chickens and

mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

exhibit a complicated process in which FGF and Wnt clocks affect the Notch clock. However, the segmentation clock model is highly evolutionarily conserved.

Signalling in separation and epithelialization of somites

The physical separation of somites depends on the pulling of cells away from each other and the formation of borders and new adhesions between different cells. Studies indicate the importance of pathways involving Eph receptor and the Ephrin family of proteins, which coordinate border formation, in this process. Also, fibronectins and

cadherin Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ...

s help the appropriate cells localize with each other.

Specification and differentiation

Regarding the paraxial mesoderm from which somites form, fate mapping experiments at the

blastula Blastulation is the stage in early animal embryonic development that produces the blastula. In mammalian development, the blastula develops into the blastocyst with a differentiated inner cell mass and an outer trophectoderm. The blastula (fr ...

stage show pre-somitic mesoderm progenitors at the site of gastrulation, referred to as the primitive streak in some organisms, in regions flanking the organizer. Transplant experiments show that only at the late

gastrula Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of Cell (biology), cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered e ...

stage are these cells committed to the paraxial fate, meaning that fate determination is tightly controlled by local signals and is not predetermined. For instance, exposure of pre-somitic mesoderm to Bone morphogenetic proteins (BMPs) ventralizes the tissue, however ''in vivo'', BMP antagonists secreted by the organizer (such as Noggin and chordin) prevent this and thus promote the formation of dorsal structures.

Termination of somitogenesis

It is currently unknown by what mechanism somitogenesis is terminated. One proposed mechanism is massive cell death in the posterior-most cells of the pre-somitic mesoderm so that this region is prevented from forming somites. Others have suggested that the inhibition of BMP signaling by Noggin, a Wnt target gene, suppresses the epithelial-to-mesenchymal transition necessary for the splitting off of somites from the bands of pre-somitic mesoderm and thus terminates somitogenesis. Although endogenous retinoic acid is required in higher vertebrates to limit the caudal Fgf8 domain needed for somitogenesis in the trunk (but not tail), some studies also point to a possible role of retinoic acid in ending somitogenesis in vertebrates that lack a tail (human) or have a short tail (chick). Other studies suggest termination may be due to an imbalance between the speed of somite formation and growth of the pre-somitic mesoderm extending into this tail region.

Somitogenesis in different species

Different species have different numbers of somites. For example, frogs have approximately 10, humans have 37, chicks have 50, mice have 65, and snakes have more than 300, up to about 500. The differences in the number of somites between species is thought to be largely due to evolutionary changes in the frequency of the segmentation clock, and changes in the duration of somitogenesis. Somite number is unaffected by changes in the size of the embryo through experimental procedure. Because all developing embryos of a particular species form on average the same number of somites, the number of somites present is typically used as a reference for age in developing vertebrates.

References

{{reflist Embryology