Formation of the Notochord, the Somites, and the Neural Tube

A detailed description of the peculiar embryological events that give rise to the skull and vertebral column would go beyond the scope of this chapter. Nevertheless, the most salient steps are synthesized in a simplified manner to get an approximate picture of the entire process.

During the first 4 days after fertilization, the human embryo forms a mass of ∼32 cells, the blastocyst. The blastocyst is a cystic cavity with a wall formed by a layer of cells and an inner mural nodule consisting of a mass of cells, the embryonic cell proper. Attachment to the uterine wall occurs around the fifth day, and implantation in the uterus happens within the second week of gestation. The cyst grows and evolves to a formation that contains two cavities—the amnionic sac and the yolk sac—separated by a disk of two layers of cells. Once this two-layered cyst is implanted in the uterus, a cavity called the chorion forms around it. The cyst stays connected to the uterus by the stalk that will become the umbilical cord ( Fig. 2.1 ).

Gastrulation, which occurs during the third week of gestation, is the process that transforms the two-layered embryonic disk into a three-layered structure, or germ layer, made of ectoderm, mesoderm, and endoderm.4

During the third week of gestation, a definite noto-chord forms in the mesoderm between the ectoderm and endoderm. It is represented by a longitudinal tube of cells with a virtual central canal, which is located in the center of the embryonic disk along its major axis. (The term disk is used for ease of understanding. In this discussion, it indicates the relatively flat, round structure of the initial germ layer, even though a major axis, and thus a rather oval shape and loss of the flatness develops with craniocaudal differentiation and further development.)

On both sides of the notochord, the mesoderm differentiates into three main areas: the paraxial, intermediate, and lateral mesoderms. The paraxial mesoderm divides on either side of the notochord into 42 to 44 pairs of somites (specialized cell accumulations). Development of the somites occurs in a craniocaudal fashion, and the number of somites can be used to estimate embryonic age. The first somites, and thus the cranialmost, appear in the third week of gestation, and the most caudal and last ones will have formed by the end of the fifth week. The somites are the precursors of the occipital bone, the vertebrae, other bony structures of the thorax, and the associated musculature of these structures.

Each somite differentiates into two parts: a sclerotome, which is located medially, next to the notochord, and a dermomyotome, located laterally. The cells of the sclerotome are responsible for the formation of the bone, and the dermomyotomes form muscle cells and the over-lying dermis of the skin.

In the meantime, between the second and third weeks of gestation, and parallel to the formation of the noto-chord and the somites, the ectoderm above the notochord thickens and differentiates into neural ectoderm. By the end of the third week of gestation, the neural tube will have formed from this neural ectoderm and will overlay the notochord, suspended in the mesodermal layer. This process is called neurulation. The ectoderm from which the neural tube derived will have re-formed a continuous layer above the neural tube.

The third week of gestation is a crucial period for the formation of the CVJ and vertebral column because three important processes take place contemporaneously: definite formation of the notochord, formation and closure of the neural tube lying right above it, and formation and progressive appearance of the paired somites on either side of the notochord and neural tube ( Fig. 2.2 ).

Yet another event takes place in the third week of gestation that affects the somites as they progressively appear and differentiate into sclerotomes and dermomyotomes: segmentation, which characterizes the membranous stage of development and demarcates the division between the skull and vertebral column.5

Segmentation

As already mentioned, the somites differentiate into a medial part, the sclerotomes, and a lateral part, the dermomyotomes. Subsequently, the sclerotomes migrate medially and surround the notochord and the neural tube, forming a continuous mesodermal sheath and giving rise to a membranous basioccipital bone cranially and a membranous vertebral column below. The dermomyotomes will develop into the cervical musculature and overlying skin in the region.

Sclerotomes 1 to 5 form the basioccipital elements of the skull. Sclerotomes 1 to 4 give rise to the basioccipital (midline segment that lies just ahead of the foramen magnum), exoccipital (lateral margins of the foramen magnum and superior part of the occipital condyles and jugular tubercles), and supraoccipital (posterior boundary of the foramen magnum) centers. Sclerotome 5 is highly specialized because it is the first one to form a motion segment and starts the process of segmentation.

Segmentation of a sclerotome is a process in which proliferation leads to a more loosely packed cellular area in the cranial half of the sclerotome and a more densely packed area in its caudal half. As segmentation progresses, the loose cranial part and the dense caudal part will eventually separate, and the dense caudal part of one sclerotome will fuse with the loose cranial part of the one below. The splitting, and thus segmentation, of a sclerotome occurs in the area in which the future spinal nerve will transit.

In subaxial spinal development, the intervertebral disk develops, around and including the notochord, in the gap created by the segmentation of a sclerotome into cranial and caudal parts. The process can therefore be described in the following way.

Division of a sclerotome into cranial and caudal parts at the passage point of the developing spinal nerve leads to formation of a disk in the gap created by fusion of the caudal half of the sclerotome with the cranial half of the following one, forming a vertebra. This cranial half of the following sclerotome was created through division from its inferior half. A disk will form in the gap, perpetuating this process caudally ( Fig. 2.3 ).

It is important to focus on this process because it takes place in the same regular fashion at the CVJ, even though it leads to a very particular expression.6

As stated previously, sclerotome 5 plays a key role, because it starts segmentation.

Sclerotomes 1 to 4 do not undergo segmentation and, by simply fusing one with the other, give rise to the occipital bone. The fifth sclerotome, however, will divide. Its loose cranial half will fuse with sclerotome 4 and give rise to the most caudal part of the occipital condyles and foramen magnum. Its dense caudal half will give rise to the cranial part of the atlas and the tip of the axis odontoid process. It is exactly at this point and in this particular moment of embryological development that the CVJ is formed, by segmentation of sclerotome 5.

According to the previously described regular subaxial development of vertebrae and disks, it should be expected that a disk forms in the gap created by the segmentation of the fifth sclerotome into cranial and caudal parts. Obviously, there is no disk between the occiput and the atlas, but given the fact that the apical ligament has been found to contain notochordal tissue, it can be regarded as a rudimentary intervertebral disk, along with the rest of the ligamentous apparatus.7

In sclerotome 6, segmentation gives rise to a cranial half that forms the caudal part of the atlas and the odontoid process of the axis; the caudal half will form the cranial half of the body of the axis, and the cranial half of sclerotome 7 after segmentation will form the caudal half of the axis. The CVJ is thereby completed ( Fig. 2.4 ).

It can thus be stated that segmentation gives rise in sclerotome 5 to the articulation between the occipital condyles and the atlas, in sclerotome 6 to the articulation between the atlas and the axis, and in sclerotome 7 to the articulation between the axis and C3. Again, at the level of segmentation of sclerotome 6, an intervertebral disk could be expected, and indeed at birth a cartilaginous band between the odontoid process (deriving from the cranial half of sclerotome 6) and the cranial part of the axis body (deriving from the caudal half of sclerotome 6) represents a vestigial disk, referred to as a neural central (or subdental) synchondrosis. This line lies below the anatomical base of the odontoid and fuses through ossification between 3 and 6 years of age in most children, as discussed in the following section.