Chapter 2: Basic Embryology

Adult anatomy makes much more sense once you know where each structure came from. Why are the vertebrae segmented? Why does one nerve supply a strip of skin and the muscle beneath it? Why is the heart on the left? The answers are set in the first eight weeks of development, and this chapter covers the first three of them: from fertilization to the three germ layers and the first body plan.

Fertilization

Fertilization is the meeting of a sperm and an oocyte. It usually takes place in the ampulla of the uterine (fallopian) tube, and it has four steps:

1. Capacitation. Sperm freshly deposited in the female tract cannot fertilize. Over several hours in the uterus and tube, cholesterol and glycoproteins are stripped from the sperm head membrane, making it ready to react.
2. Acrosome reaction. When the capacitated sperm binds the zona pellucida, the acrosome (a cap of enzymes over the sperm nucleus) releases its enzymes. They digest a path through the zona.
3. Fusion. The sperm and oocyte membranes fuse and the sperm nucleus enters the oocyte. The oocyte, arrested in its second meiotic division, now completes meiosis II.
4. Cortical (zona) reaction. Cortical granules just under the oocyte membrane release lysosomal enzymes into the space around it. These change the zona pellucida so that no other sperm can bind or penetrate it, which prevents polyspermy.

The male and female pronuclei then meet, their chromosomes combine, and the cell is now a diploid zygote. Fertilization restores the diploid chromosome number, determines chromosomal sex (by the X or Y carried by the sperm) and starts cleavage.

Week 1: cleavage to blastocyst

• Cleavage. The zygote divides repeatedly while still inside the zona pellucida, so the cells (blastomeres) get smaller with each division and the embryo does not grow in size.
• Compaction. From about the 8-cell stage the blastomeres flatten against each other and bind tightly.
• Morula. At about 12–16 cells (around day 3) the embryo is a solid ball called the morula, which enters the uterus. Its cells already fall into two groups:
  • the inner cell mass, which becomes the embryoblast (the embryo itself);
  • the outer cell mass, which becomes the trophoblast (the embryonic part of the placenta).
• Blastocyst. Fluid seeps in and forms a cavity, the blastocoele. The embryo is now a blastocyst: an outer trophoblast shell with the embryoblast gathered at one pole.
• Implantation. The blastocyst sheds the zona pellucida and attaches to the endometrium around day 6, usually on the posterior wall of the uterine body. It is fully embedded by the end of week 2.

Week 2: the bilaminar disc

Week 2 is often called the "week of twos", because almost everything splits in two:

• The trophoblast divides into an inner, cellular cytotrophoblast and an outer syncytiotrophoblast, a mass of fused cells that erodes into the endometrium and its blood vessels. The syncytiotrophoblast produces hCG, the hormone detected by pregnancy tests.
• The embryoblast divides into two layers, the bilaminar germ disc:
  • epiblast: tall columnar cells facing the future amniotic cavity;
  • hypoblast: small cuboidal cells facing the blastocoele.
• Two cavities form. The amniotic cavity opens within the epiblast. Hypoblast cells spread to line the blastocoele, turning it into the exocoelomic cavity (primitive yolk sac).

Week 3: gastrulation, the three germ layers

Gastrulation turns the two-layered disc into three layers. It is the defining event of week 3.

1. A thickened groove, the primitive streak, appears in the midline of the epiblast at the caudal end of the disc. At its cranial end is a raised primitive node with a small primitive pit. The streak fixes the body axes: cranial–caudal, right–left and dorsal–ventral.
2. Epiblast cells migrate toward the streak, dip through it (invagination) and spread out beneath:
   • the first cells displace the hypoblast and become the endoderm;
   • later cells settle between epiblast and endoderm as the mesoderm;
   • the epiblast cells that stay on the surface become the ectoderm.

So all three germ layers come from the epiblast.

The notochord

Cells passing through the primitive node migrate cranially in the midline and form a rod, the notochord. It has two jobs to remember:

• Induction. The notochord secretes Sonic hedgehog (SHH), which signals the overlying ectoderm to become neural plate. This starts neurulation.
• Fate. Most of the notochord disappears as the vertebral bodies form around it. What survives becomes the nucleus pulposus of each intervertebral disc (see chapter 3).

Ectoderm and neurulation

Neurulation is how the ectoderm over the notochord becomes the central nervous system:

1. The notochord induces the overlying ectoderm to thicken into the neural plate.
2. Its edges rise as neural folds, leaving a neural groove in the midline.
3. The folds meet and fuse, forming the neural tube. Fusion starts in the future neck region around day 22 and proceeds in both directions.
4. The open ends, the cranial (anterior) neuropore and caudal (posterior) neuropore, close last: the cranial one around day 25 and the caudal one around day 28.

Cells at the crest of each fold detach as the neural crest and migrate throughout the body.

Neural tube defects

If the neural tube fails to close, the result is a neural tube defect (NTD):

• failure of the cranial neuropore → anencephaly (the forebrain and skull vault do not form; not compatible with life);
• failure of the caudal neuropore → spina bifida, ranging from a hidden defect of the vertebral arch (spina bifida occulta) to an open sac of meninges and spinal cord on the back (myelomeningocele).

Low maternal folic acid (vitamin B9) is the major preventable cause. The tube closes by day 28, often before a pregnancy is recognised, so folic acid supplements are recommended before conception and through the first trimester.

Mesoderm

The mesoderm on each side of the notochord organises into three longitudinal strips, from medial to lateral.

Paraxial mesoderm → somites

The paraxial mesoderm beside the neural tube segments into paired blocks, the somites (about 42–44 pairs appear, though some later regress). Each somite divides into three parts:

• Sclerotome → the vertebrae and ribs (cartilage and bone of the axial skeleton). Each vertebral body forms from the lower half of one sclerotome fused with the upper half of the next, which is why spinal nerves exit between vertebrae.
• Dermatome → the dermis of the skin of the back.
• Myotome → skeletal muscle of the trunk and limbs.

Each somite keeps its own spinal nerve. That is why an adult spinal nerve supplies a strip of skin (a dermatome in the clinical sense) and a group of muscles (a myotome) from the same segment.

Intermediate mesoderm

The intermediate mesoderm forms the urogenital system: the kidneys and ureters, the gonads (testis and ovary), and their duct systems.

Lateral plate mesoderm

The lateral plate splits into two layers with a cavity between them, the intraembryonic coelom (the future body cavities):

• Somatic (parietal) layer, against the ectoderm → the lining of the body wall (parietal pleura and peritoneum), and the bones and connective tissue of the limbs and body wall. The limb muscles, by contrast, come from myotomes that migrate into the limb buds.
• Splanchnic (visceral) layer, against the endoderm → the heart, the smooth muscle and connective tissue of the gut and airway walls, the visceral pleura and peritoneum, and the cortex of the adrenal gland.

Endoderm

As the embryo folds, the endoderm is drawn into a tube: the primitive gut. It is closed at the cranial end by the oropharyngeal membrane (future mouth) and at the caudal end by the cloacal membrane (future anus). The gut is divided into three parts, each with its own artery, which remains true in the adult:

Other endodermal derivatives include the lining of the middle ear and auditory tube, the thyroid, parathyroid glands and thymus, and the lining of the bladder and urethra. Endoderm forms only the epithelium of these organs; their muscle and connective tissue come from splanchnic mesoderm.

Summary: germ layer derivatives

Lateralization: why the heart is on the left

The body looks symmetrical from outside but not inside: the heart points left, the liver sits right, and the stomach lies in the left upper abdomen. This left–right asymmetry is set during gastrulation.

• Cilia on the primitive node beat in a way that sweeps fluid to the left.
• On the left side, FGF8 from the node and primitive streak switches on Nodal and Lefty2, which in turn switch on the transcription factor PITX2, the master gene for "left" structures.
• Lefty1 along the left side of the midline (and SHH from the notochord) acts as a barrier that keeps these left signals from spreading to the right.
• Serotonin (5-HT) is concentrated on the left and is needed for this signalling; the enzyme monoamine oxidase (MAO), active on the right, breaks it down.

When this pathway fails, organs can be mirror-reversed (situs inversus) or randomly arranged (heterotaxy), often with heart defects. Defective cilia, as in primary ciliary dyskinesia, can cause situs inversus.

Because serotonin signalling helps set left–right patterning, selective serotonin reuptake inhibitors (SSRIs) taken in early pregnancy have been associated with laterality and heart defects. The deck puts this as "pregnant women must not take SSRIs". In practice the decision weighs this risk against the risk of untreated depression and is made with the treating doctor.

Key teaching point

The adult body plan is visible in the three-week embryo. The notochord ends as the nucleus pulposus. Somites explain why vertebrae, skin strips and muscle groups share segmental nerves. The gut's three parts explain its three arteries. Chapters 3 to 7 build on these origins.