The Third Week Of Life:


Professor Alfred Cuschieri
Department of Anatomy
University of Malta



In most animals the blastula develops into a gastrula that consists of a distended sac-like structure with an opening at one end.  Important changes occur at the opening of the gastrula involving migration of cells and leading to the formation of a trilaminar embryo.  In humans the embryo does not form a gastrula, but the changes leading to the formation of the trilaminar embryo occur and are known as gastrulation.

By the 13th day the embryo has the form of a bilaminar disc with a distinct polarity.

The amniotic cavity and the yolk sac can be visualised as two hemispheres, with their apposed surfaces forming the bilaminar embryo.

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The main changes associated with gastrulation affect the epiblast.




When viewed from above, i.e through the amniotic cavity, the epiblast appears as an oval disc.  The connecting stalk marks the caudal end of the embryo. 

The primitive streak appears in the caudal half of the epiblast, and lies along the cranio-caudal axis.

It consists of :

·        The primitive node and pit

·        The primitive streak and groove

The buccopharyngeal membrane and the cloacal membrane are two areas that mark the future mouth and anus respectively. They are situated in the midline at the cranial and caudal ends respectively.



Three important processes occur at the primitive streak:


1.    Cell proliferation - causes heaping up of the cells and is the source of a new layer of cells

2.    Cell migration by amoeboid movement – the cells insinuate themselves between the epiblast and hypoblast

3.     Cell determination - the cells arising from the primitive streak are determined to give rise to different rudiments


The notochord


The notochordal process grows out from the primitive node grows as a rod of cells that migrate cranially in the midline. Its growth is limited by the buccopharyngeal membrane.  The most cranial part of the notochord is termed the prochordal plate.

The notochordal process becomes canalised forming a hollow tube communicating with the primitive pit.  The floor of the tube and the underlying endoderm break down, and a temporary communication is established between the amniotic cavity and the yolk sac.  This communication is termed the neurenteric canal.  It is very short-lasting as the notochord proliferates to form a solid cord.




Intra-embryonic mesoderm


While the cells from the primitive node proliferate and migrate to form a midline notochord,  cells from the primitve streak migrate laterally and cranially between the epiblast and hypoblast to form the intra-embryonic mesoderm.  The meosderm lies on either side of the notochord, the  buccopharyngeal membrane, and the cloacal membrane.  The epiblast and hypoblast remain in contact at the buccopharyngeal and cloacal membranes, which are not separated by mesoderm.  






Growth of the bilaminar disc.


As the intra-embryonic mesoderm spreads out from the primitive streak, the whole embryo increases in size and the primitive streak becomes relatively smaller.  When the process of gastrulation is complete the primitive streak disappears.






Changes consequent on gastrulation


With the process of gastrulation the following changes have occurred:

1.    The embryo becomes a trilaminar embryo that is still in the form of a flat disc.

2.    Epiblast and hypoblast are now known as ectoderm and endoderm respectively.

3.    Mesoderm does not extend between epiblast and hypoblast at the buccopharyngeal and cloacal membranes

4.    Intra-embryonic mesoderm merges with the extra-embryonic mesoderm at the periphery of the embryonic disc

5.    Gastrulation converts the embryo into a trilaminar disc

6.    Gastrulaton can be inhibited by drugs that interfere with actin filament formation – they inhibit cytokinesis and cell migration

7.    The migrating cells can be traced experimentally in chick embryos by transplanting embryonic cells of the primitive streak from quail embryos.  Quail cells have nuclei that are morphologically different fromthose of chick cells and can be distinguished microscopically.


Mesoderm  forms several distinct masses:









I                     Mesoderm in the lateral part of the embryo is divided into three distinct longitudinal masses:

(a)    Paraxial mesoderm

-  a longitudinal column of cells that lies next to the notochord

- it gives rise to the axial skeleton and skeletal muscle

-  it becomes segmented

(b)   Intermediate cell mass

-  it gives rise to the genitourinary system

(c)    Lateral plate mesoderm

- gives rise to body wall structures

-  is continuous with the extra-embryonic mesoderm

- splits into two layers enclosing the intra-embryonic coelom



II                 The Septum transversum

-  Forms a transverse bar of mesoderm cranial to the buccopharyngeal membrane

–       Is the only place where mesoderm extends across the midline

–       Is the region where the future heart, diaphphragm and liver will develop.


III              The Caudal mesoderm

-  Lies caudaly lateral to the primitive streak

–       Is the region that gives rise to the  caudal structures including the pelvic viscera.




The paraxial mesoderm is segmented


Of the three blocks pf mesoderm only the paraxial mesoderm is segmented.  The segments are termed somites. The first somite appears on day 20 at the cranial end close to the prochordal plate.

Somites develop in cranio-caudal sequence to form 42 to 44 somites by day 30. 

The somites are:

4 occipital,  8 cervical,  12 thoracic,  5 lumbar,  5 sacral, and   3 coccygeal. 

A few other somites at the caudal end degenerate. 






A coelom develops  in the lateral plate mesoderm.


The intra-embryonic coelom develops in the lateral plate mesoderm and extends into the transverse mesoderm.  It develops by the breaking down of cells by apoptosis (programmed cell death).  The intra-embryonic coelom is shaped like an inverted U-tube, and is divided into three parts: 

(a)    The bend is situated in the transverse mesoderm and is dilated to form the pericardial cavity.  

(b)    The stems of the U-tube extend into the lateral plate mesoderm were it forms the paired pleuro-peritoneal canals. 

(c)    The distal (caudal) end of the intra-embryonic coelom communicates laterally with the extra-embryonic coelom.  


The Concept of Induction


The embryological processes of development follow a definite co-ordinated sequence.  Induction is the stimulation of a group of cells to undergo differentiation by another closely-situated group  of cell

An example of induction is the initial development of the central nervous system.  Here the notochord (a midline rod of cells) stimulates the overlying ectoderm to differentiate into neurectoderm.




The Neural Plate










The neurectoderm is now termed the neural plate.  Like the notochord it is limited craniallly by the buccopharyngeal membrane and caudally by the cloacal membrane. 

The cranial end of the neural plate

·        is  broader than the more caudal part

·        overlies the prochordal plate

·        gives rise to the brain

The main part :

·        Overlies the notochord

·        Gives rise to the spinal cord

The caudal end of the embryo continues to elongate by growth from the primitive streak




Genetic organization of the Primitive Streak.


The diagram below shows that primitive node and streak release a number of genetically controlled factors.  These are shown on the right of the diagram together with their main function in patterning of the embryo. It is not important to memorise the strange names given to these factors.   Note how these factors play a critical role in determining the cranio-caudal axis of the embryo.  The primitive node is the first and central structure.  It  determines the growth of the notochord cranially (by factor NHF-3b) and of the primitive streak caudally (by the factor nodal) and the body axis (by the factor goosecoid).  It is also responsible for inducing the cells to become motile and migrate to pre-determined sites (by the factor T-gene).  Note also how the prochordal plate determines the cranial end of the embryo (by factor Lim-1).













Establishment of right-left asymmetry.


This is the second critical event in patterning of the embryo, and in determining the asymmetric development of the viscera on the right and left sides of the body.  This right left differentiation is determined by several laterality genes, the main ones of which are show below.


The signalling molecule known as sonic hedgehog (Shh) is expressed bilaterally and symmetrically.  Activin is expressed only on the left, inhibits the further action of Shh, and causes a differential expression of the growth factor nodal.  There are also genes  that specifically determine development of structures only on the left side.  These have been called Inversus viscerum and left-right dynein.  Mutations of these genes cause “situs inversus” where the apex of the heart, the spleen and the stomach are situated on the right instead of of the left.














There are three big classes of factors that are involved in the genetic control of early embryonic development:


1. Transcription factors.  These are factors that :

·        Act within the cells that produce them

·        Bind to DNA and controls transcription of other genes

·        Initiate patterns of gene expression

There are various families of transcription factors:

Homeodomain - Hox gene family

Zinc finger – a family of steroid-binding transcrition factors

Basic helix-loop-helix protein – myogenic regulatory factors

Winged helix – hepatocyte nuclear factor-3


2. Signalling molecules.  These are  molecules that:

·        Exert their effect on other cells

·        Mediate most interactions e.g. induction

·        Bind to trans-membrane receptor molecules

·        Are mainly growth factors

Examples are:

Transforming growth factor-B (TGF-B) – activate posterior Hox genes

Fibroblast growth factor (FGF) – activate anrterior Hox genes

Nerve growth factor (NGF) – stimulate growth of axons

Hedgehog proteins – mediate early inductive interactions


3. Cell adhesion molecules. 

·        They are responsible for specific cell aggregation and sorting

·        Some are calcium-dependent  (Cadherins)

·        Some are calcium-independent (CAM)

An example is the differentiation of the epiblast into neurectoderm (induced by the notochord) and skin ectoderm by the differential expression of N-CAM and L-CAM in the neurectoderm and skin ectoderm respectively.