Human Embryology

Introduction

In obstetrics, it is common to use 280 days (40 weeks) from the first day of the last menstrual period (LMP) to estimate the delivery date of a full-term pregnancy. This period has also become a convenient, but inaccurate, description of the number of weeks of ‘pregnancy’. This is an obvious source of confusion, since embryologists refer to the number of gestational days (GD), that is, days since fertilization, when discussing early human development. Since conception requires male and female gametes to be in the same place (the ampulla of the fallopian tube) at the same time (within a few hours of ovulation and within 6 days of intercourse), it can be approximated to:

• ~14 days after the first day of the LMP, that is, an estimate of the day of ovulation in a woman with a regular 28-day cycle

• the day of ovulation as judged by a change in basal body temperature, serum luteinizing hormone (LH) and/or estrogen-to-progesterone ratios

• six days prior to the rapid increase in chorionic gonadotrophin levels that is associated with implantation of the embryo.

In most pregnancies, only the first of these options is available; thus 8 weeks of ‘pregnancy’ implies 42 GD.

Nomenclature

Embryology has a dense, classically based nomenclature. Attempts at standardisation have often led to the same structure having at least two different names (e.g., yolk sac and umbilical vesicle; branchial and pharyngeal arches) and/or the same structure changing its name at different stages of development (e.g., allantois → urachus → medial umbilical ligament). This complexity can be disheartening. Thus, only the most up-to-date terms will be used and will be related to the mature tissues, whenever possible. Some transient structures are important in understanding malformations, which will be highlighted here.

The transition from embryonic to fetal life is at ~56 GD (i.e., ~10 weeks post-LMP). This is an arbitrary but useful boundary that is based on the fact that 90% of adult structures are recognisable at this stage. One of the most important concepts in embryogenesis is the establishment of the three main embryonic axes: (1) rostrocaudal (more correctly termed anteroposterior in early embryogenesis), (2) dorsoventral and (3) left–right ( Box 40.1 , Fig. 40.1 ).

Fertilization to Implantation (0–6 GD)

In vitro fertilization has greatly increased our understanding of the early cellular and molecular events in human embryogenesis ( Fig. 40.2 ). Sadly for the male ego, the sperm has only three essential roles in embryogenesis:

• 1

  To stimulate a change in the zona pellucida that prevents further sperm entering the cell

• 2

  To deliver a paternally imprinted haploid genome ( Box 40.2 ) in order to reconstitute a diploid chromosome number

  Box 40.2

  Imprinting

  The male and female gamete both contain 23 chromosomes, one copy of each autosomal chromosome (numbered 1–22 in decreasing order of size) and one sex chromosome (X in egg and X or Y in sperm). The DNA sequence of each pair of chromosomes is essentially identical, but the maternal copy we inherit functions differently from the paternal copy; indeed, they can be considered antagonistic. For example, the short arm of chromosome 11 contains the gene insulin-like growth factor type 2 ( IGF2 ). Although there are two copies of IGF2 in each cell, only one is ever active – this is always on the paternally inherited chromosome 11. IGF2 produces a protein that promotes fetal growth (the ‘male’ drive) but is silenced on the maternal copy (the ‘female’ drive). This particular mechanism probably evolved to balance the conflict between the advantage to the male of having a large offspring at birth and the risk to the mother of delivering such a large offspring.

  Differential gene activation is the result of the silencing of one copy of a gene via covalent modifications of both the DNA itself (methylation) and histone proteins (acetylation), which are intimately associated with the double-stranded DNA molecule. These parent-of-origin-specific modifications are known as ‘genomic imprinting’. Beckwith-Wiedemann syndrome is caused by specific genetic mutations that result in a fetus having two active copies of IGF2 . The result is an infant that is large for gestational age and who is prone to tumour formation, particularly Wilms tumour. Several other examples of imprinting mutations are known.

• 3

  To stimulate the second meiotic division in the egg with subsequent production of the second polar body.

In contrast to the sperm, the egg is a complex cell with many subcompartments, each with a critical role. At the most basic level, the egg carries a maternally imprinted haploid genome ( Box 40.2 ). It also determines the orientation of at least one of the ‘axes’ in the early embryo (see Box 40.1 ) and provides all of the ribonucleic acid (RNA) and protein synthesis requirements until the embryonic genome becomes transcriptionally active at 2 to 3 days post-fertilization.

The first mitotic division occurs 36 hours after fertilization. The next four mitoses are at intervals of ~17 hours and produce a ball of cells called a blastomere. After the fifth mitotic division, the blastomere becomes polarized as a sphere with a single-cell-layered wall (trophoblast) and an inner cell mass. The inner cell mass of this blastocyst contains the cells that will form the embryo itself. The 128 cells that are present following the seventh mitotic division still occupy the same volume as the initial fertilized egg, that is, there has been no physical growth. The embryo sheds the zona pellucida at about this time, a process termed fancifully as ‘hatching’. Over these first 5 days, the embryo is transported along the fallopian tube and becomes attached to the uterine wall around 6 GD.

Implantation and Formation of the Germ Layers (7–18 GD)

At implantation, the trophoblast buries itself in the endometrium. The embryo thus gains access to the maternal circulation and behaves as an efficient paracytic organism, which enables a very rapid period of growth. The inner cell mass begins to differentiate and the embryo takes on the appearance of a disc consisting of two layers of morphologically distinct cells: the epiblast (the dorsal region) and the hypoblast (the ventral region, Fig. 40.3A ). This is the first real evidence of embryonic polarity. The largest embryonic cavity at this stage is the umbilical vesicle, which is lined with hypoblast cells. The amniotic cavity begins to form by 9 GD and is lined with epiblast cells.

By day 16, the embryonic disc takes on an oval shape and a second axis (rostrocaudal or head–tail axis) becomes apparent. This is accompanied by a process known as gastrulation, during which cells from the epiblast migrate towards a groove in the caudal end of the disc, known as the primitive streak (see Fig. 40.3B ). The migrating cells pass though the primitive streak and form a new embryonic compartment, or ‘germ layer’, called the mesoderm. The dorsal epiblast now becomes the embryonic ectoderm and the hypoblast is replaced by embryonic endoderm. The embryo now has three ‘germ’ layers bounded by the umbilical vesicle ventrally and the amniotic cavity dorsally.

Organogenesis (19–56+ GD)

The outline of organogenesis given here is necessarily brief and is divided into five main areas:

• 1

  Neural tube and brain

• 2

  Gut tube and derivatives

• 3

  Heart and liver

• 4

  Craniofacial structures

• 5

  Limbs and skeletal muscle.

Neural tube and brain

Formation of the neural tube and primitive brain is the first evidence of organogenesis. It begins at 19 GD, when a midline groove forms on the dorsal ectodermal surface, rostral to the primitive streak. This change in the surface ectoderm is induced by a strip of specialized midline mesodermal cells called the notochord ( Fig. 40.4 ). Two important paired structures form on either side of this groove:

• The neural folds

• The somites.

The neural folds grow rapidly and begin to fuse across the midline in the cervical region to form the neural tube by 22 GD. At the same time, paired segmental condensations of the mesoderm (somites) are beginning to form blocks of tissue on either side of the midline (paraxial mesoderm). A new pair of somites appears every 6.6 hours in a rostrocaudal direction. The somites are critical for establishing the adult body plan. Their formation is an example of repeated segment (metameric) pattern formation during embryogenesis ( Box 40.3 ).

Box 40.3

Pattern formation

Pattern formation is a molecular concept whereby the future fate of a group of cells is determined by specific patterns of gene expression or activity prior to any morphological change being detected. The most striking patterns involve the activation of specific transcription factors induced by gradients of signalling molecules within the embryo. The best-known example involves Hox gene determination of the identity of individual somites along the rostrocaudal axis. Later in development, Hox genes also play a role in patterning the limb bud. However, many other classes of transcription factors are vital for pattern formation.

Defects in these patterning processes underlie many types of malformation. For example, mutations in one allele of the transcription factor PAX6 result in failure of iris formation (aniridia) and homozygous mutations cause complete absence of the eye (anophthalmia; Fig. 40.5 ), whereas mutations in the related gene PAX9 cause the absence of particular teeth (hypodontia). Mutation in a single gene can produce a specific syndrome characterised by a particular combination of malformations. This suggests that the mutated gene may be used at different stages of development and in different tissues. Other malformation combinations may be the result of deletion of a chromosomal region that causes adjacent genes to be lost, for example, WAGR syndrome is caused by a deletion on chromosome 11p13 and is characterised by aniridia and Wilms tumour as a consequence of both WT1 and PAX6 mapping to 11p13.

Fusion of the neural tube proceeds rapidly in both rostral and caudal directions. This apparently simple tube will give rise to the entire central nervous system (CNS). At either end of the embryo, the neural tube remains open for a short time. These openings are referred to as the rostral and caudal neuropores. The rostral neuropore closes by 23 GD; failure of this process results in one of the most severe of human malformations, anencephaly. The caudal neuropore is the last part of the neural tube to close at 26 GD; failure of this closure leads to spina bifida.

The rostral half of the neural tube is more complex and forms the future brain. The caudal part forms the spinal cord. In common with many other embryological structures, the formation of the CNS is best viewed as a tube which is segmented along the rostrocaudal long axis. Each linear segment then differentiates dorsoventrally to produce the final adult form. At day 26, the CNS is a tube with four main segments:

• 1

  Forebrain – prosencephalon

• 2

  Midbrain – mesencephalon

• 3

  Hindbrain – rhombencephalon

• 4

  Spinal cord.

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