Describe the events of the second and third weeks of development. Explain gastrulation, the notochord and neurulation.

The Second Week — the “week of Twos”

• Trophoblast splits into two — cytotrophoblast and syncytiotrophoblast
• Embryoblast splits into two — forming the bilaminar disc: epiblast (columnar, toward the amniotic cavity) and hypoblast (cuboidal, toward the yolk sac)
• Two cavities appear — the amniotic cavity and the primitive yolk sac
• Extraembryonic mesoderm splits into two — somatopleuric and splanchnopleuric, enclosing the chorionic cavity (extraembryonic coelom)
• Prochordal plate forms — a thickening of hypoblast marking the future mouth and the cranial end
• The embryo remains attached by the connecting stalk

The Third Week — the “week of Threes”

• All three germ layers arise from the epiblast — a statement students find surprising but is the single most important fact about gastrulation
• The primitive streak establishes the body axes — cranio-caudal, dorsoventral, and left–right
• Two membranes have no mesoderm — the buccopharyngeal membrane cranially and the cloacal membrane caudally; they later break down to form the mouth and the anus

The Notochord

• Cells from the primitive node migrate cranially to form the notochordal process, which becomes the definitive notochord
• Functions — it forms the primitive axis of the embryo, induces the overlying ectoderm to form the neural plate, and induces the vertebral bodies
• Fate — it disappears where the vertebral bodies form, and persists only as the nucleus pulposus of the intervertebral disc

Neurulation

• Neural crest cells separate from the crests of the folds and migrate widely
• Neural crest derivatives — dorsal root and autonomic ganglia, Schwann cells, suprarenal medulla, melanocytes, meninges (pia and arachnoid), odontoblasts, and most of the bones and connective tissue of the face
• The neural crest is sometimes called the fourth germ layer for the breadth of its contribution

Mesoderm and Somites

• The first pair of somites appears on day 20, and thereafter about three pairs a day, reaching 42–44 pairs
• Somites are used to age the embryo in the fourth and fifth weeks
• The segmental origin of the myotomes explains the segmental nerve supply of muscle, and so the dermatomes and myotomes of clinical neurology

Establishment of Left–right Asymmetry and Early Circulation

• Cilia at the primitive node beat leftward, creating a flow that establishes the left–right axis — the earliest sign of asymmetry in the embryo
• Their failure gives situs inversus, and in Kartagener syndrome the same dynein defect that immobilises respiratory cilia gives bronchiectasis, sinusitis and situs inversus together
• Blood islands appear in the extraembryonic mesoderm of the yolk sac in the third week; the peripheral cells become endothelium and the central cells become primitive blood cells
• The heart tube forms and begins to beat on day 22 — the first organ to function, because diffusion alone can no longer supply the growing embryo
• Angiogenesis in the embryo proper follows, and the two systems join

Fate of the Primitive Streak and the Body Axes

• The primitive streak regresses caudally and normally disappears by the end of the fourth week
• Its persistence gives a sacrococcygeal teratoma, containing tissue of all three germ layers — the commonest tumour of the newborn, and commoner in girls
• HOX gene mutations cause homeotic transformations, in which one segment develops the character of another — the basis of some vertebral anomalies

Applied Aspects

• Neural tube defects — failure of neuropore closure by day 25–27. Anterior failure gives anencephaly (incompatible with life); posterior failure gives spina bifida, from occulta to meningomyelocele
• Folic acid 400 micrograms daily from before conception reduces the risk by about 70%; it must be started before the neural tube closes, which is why it is given periconceptionally rather than when pregnancy is confirmed
• Alpha-fetoprotein is raised in maternal serum and amniotic fluid in open neural tube defects
• Sacrococcygeal teratoma — a remnant of the primitive streak that fails to regress; the commonest tumour of the newborn
• Chordoma — a rare tumour of notochordal remnants, in the sacrum or the base of the skull
• Neurocristopathies — disorders of neural crest migration: Hirschsprung disease, DiGeorge syndrome, Waardenburg syndrome, neurofibromatosis
• Caudal regression syndrome — insufficient mesoderm at the caudal end of the streak; associated with maternal diabetes, and giving sacral agenesis and lower limb defects
• Situs inversus from failure of nodal cilia; usually harmless, but heterotaxy with isolated organ reversal carries a high rate of complex cardiac malformation
• Twinning after day 13 reflects incomplete splitting of the germ disc itself, and produces conjoined twins
• The notochord persists as the nucleus pulposus, and its degeneration with age underlies intervertebral disc prolapse