Embryogenesis

Abstract

Embryogenesis is the process of embryonic development occurring in the first eight weeks after fertilization. After implantation of the blastocyst in the endometrium, the embryo consists of the embryoblast and the trophoblast. While the embryoblast further develops into different structures of the body, the trophoblast is mainly involved in the development of the placenta. The amniotic cavity, yolk sac, extraembryonic mesoderm, and the chorionic cavity develop during the second week. In weeks 3 and 4, the bilaminar disc differentiates into a trilaminar embryonic disc through the process of gastrulation. A number of structures develop from the three germ layers. The nervous system also develops during weeks 3 and 4 through the process of neurulation. Weeks 5–8 are mainly characterized by organogenesis and continued differentiation of embryonic tissue.

Overview

2nd week of embryonic development (days 8–14)

3rd and 4th week of embryonic development (days 15–28)

The embryo is extremely susceptible to teratogens from week 3 to week 8, when the process of organogenesis occurs.

5th–8th week of embryonic development (days 29–56)

Weeks 5–8 of embryogenesis mainly involves organogenesis and continued differentiation of the embryo. Organogenesis is complete by the end of week 8. In the subsequent fetal period, the fetus grows and develops.

Characteristics
Week 5
  • Rapid head growth through development of the brain and facial structures
  • The mesonephros, which is formed between weeks 3 and 5, bulges in the urogenital ridge.
  • Upper and lower limb buds form and increase in size.
  • Development and differentiation of additional pharyngeal arches
Week 6
  • Digital ray development
  • Auricular hillock development, which later becomes the auricle
  • Eye is clearly recognizable through retinal pigment development
  • Back starts to straighten
  • Formation of a physiological umbilical hernia
  • Fetal heart tones are visible on transvaginal ultrasound.
Week 7
  • The proximal bones of the upper limbs start to ossify.
Week 8
  • Recognizable human form
  • Fingers are initially separated from one another by skin flaps, followed by complete separation.
  • The proximal bones of the lower limbs start to ossify.
  • Genitals have sex-specific characteristics; however, these are not yet sufficient to determine sex on ultrasound.
  • Fetal movements begin.

Embryoblast and trophoblast development

Embryoblast

In the 2nd week of embryonic development (days 8–14), the embryoblast differentiates into two layers (epiblast and hypoblast), termed the bilaminar disc. After formation of the amniotic cavity and yolk sac, the bilaminar disc is sandwiched between them.

All three germ layers (ectoderm, mesoderm, and endoderm), as well as the amniotic cavity and therefore the entire embryonic tissue, arise from the epiblast. The extraembryonic mesoderm and the yolk sac are derived from the hypoblast.

The bilaminar disc forms the dividing layer between the yolk sac and amniotic cavity.

Trophoblast

The trophoblast is the layer of cells that surrounds the blastocyst. During week 2, the trophoblast divides into two layers, the cytotrophoblast and the syncytiotrophoblast. They form the embryonic component of the placenta.

The extraembryonic coelom is also called the chorionic cavity, which is lined by the chorion.

References:[1]

Gastrulation

Gastrulation is the formation of the trilaminar embryonic disc or gastrula through the migration of epiblast cells. Epiblast cells migrate through the primitive streak between the epiblast and hypoblast layers and form an intermediate cell layer called the intraembryonic mesoderm. The hypoblast is replaced by epiblast cells, from which the endoderm arises. The original epiblast becomes the ectoderm.

All embryonic tissue originates from the epiblast!

Notogenesis

  • Definition: : development of the notochord, a rodlike structure between the ectoderm and endoderm that is essential for the development of the nervous system and primitive skeletal structures
  • Location: The notochord migrates along the primitive streak (the future craniocaudal axis), and ends at the prechordal plate. It is part of the axial mesoderm
  • Process: occurs weeks 3–4 (at the same time as development of the trilaminar embryonic disc)
    • Epiblast cells migrate from the primitive nodes and extend cranially to form the notochordal process.
    • Notochordal process margins converge until they merge into the rod-shaped notochord at the end of week 4
  • Derivatives: The nucleus pulposi of the intervertebral discs are remnants of the notochord.

The notochord degenerates during the course of embryogenesis. The nuclei pulposi of the intervertebral discs are remnants of the notochord.

Neurulation

Neurulation is the formation of the neural tube and neural crests, which are the precursors to the central and peripheral nervous systems. During this process, the surface ectoderm is also formed, which gives rise to the epidermis.

The entire nervous system develops from the ectoderm!

Neural tube defects are one of the most common CNS malformations and develop as a result of incomplete closure of the neural tube (e.g., spina bifida, anencephaly).

Branchial apparatus

Definition: An embryological structure with five paired arches composed of mesodermal and neural crest cells bound externally by an ectodermal cleft and internally by an endodermal pouch, which differentiate into various head and neck structures. The branchial apparatus is externally visible below the developing brain of a 4-week-old embryo. The fifth arch regresses in utero and does not contribute to the development of any head and neck structures.

Pharyngeal arches

Pharyngeal arch derivatives
Pharyngeal arch Nerve Artery Muscle Skeletal structure

First pharyngeal arch

(mandibular arch)

  • CN V3
  • Maxillary artery
  • Muscles of mastication
  • Mylohyoid muscle
  • Digastric muscle, anterior belly
  • Tensor tympani muscle
  • Tensor veli palatini muscle

Second pharyngeal arch

(hyoid arch)

  • Obliterates completely
  • Muscles of facial expression
  • Digastric muscle, posterior belly
  • Stylohyoid muscle
  • Stapedius muscle
  • Stapes
  • Styloid process
  • Stylohyoid ligament
  • Hyoid bones
    • Lesser horn and body

Third pharyngeal arch

  • Stylopharyngeus muscle
  • Hyoid bones: greater horn and body

Fourth pharyngeal arch

  • Middle and inferior pharyngeal constrictor muscles
  • Cricothyroid muscle
  • Palatopharyngeus muscle
Sixth pharyngeal arch

Pharyngeal pouch

The inferior parathyroid glands arise cranially (3rd pouch) but end up caudally (lower poles of the thyroid gland). The superior parathyroid glands arise caudally (4th pouch) but end up cranially (superior poles of the thyroid gland).

Pharyngeal grooves

  • Derivatives
    • The first pharyngeal groove develops into the external auditory meatus, the auditory canal, and the external aspect of the tympanic membrane.
    • The second to fourth pharyngeal grooves are obliterated in-utero by the rapid growth of the second pharyngeal arch, and they do not differentiate into any of the head and neck structures.
  • Cervical sinus
    • The second pharyngeal arch develops faster than the others → overlap and merge with the second and third arches → grooves lose their connection with the amnion → cervical sinus is formed.
    • The cervical sinus is obliterated during later development.
    • Failure of the cervical sinus to obliterate completely results in branchial cleft sinus, which can lead to lateral cervical fistula.

A lateral cervical fistula is prone to infection and is a clear indication for operative treatment!

Aortic arches

The aortic arches are blood vessels that run in between the pharyngeal pouches and form the major head and neck arteries. The arches develop in craniocaudal order, with the first two arches obliterating early and the fifth either never developing or also obliterating without giving rise to a vessel.

Aortic arches Derivatives
First
  • Maxillary artery
Second
  • Hyoid artery
  • Stapedial artery
Third
  • Common carotid
  • Proximal internal carotid
  • Sprouts the external carotid
Fourth
Sixth

Morphogenesis

Morphogenesis is the process by which the shape of an organism is generated. The embryo undergoes folding, resulting in transformation of the flat, germinal disc into an embryo that approaches the human form during the course of the pregnancy. During the folding processes, the abdominal cavity, the abdominal wall, and the gut tube are formed. At the cranial and caudal embryonic poles, there is an area devoid of the mesoderm where the endoderm and ectoderm come into direct contact with one another, called the buccopharyngeal or cloacal membrane. The mouth and anus will later form in these areas.

Body axis determination

  • Dorsoventral body axis: formed as the bilaminar disc develops
  • Craniocaudal body axis: formed by the extension of the primitive streak
    • Cranial pole: primitive nodes
  • Right-left differentiation: The positioning of unpaired chest and abdominal organs is determined by asymmetric expression of signaling molecules in the lateral plate mesoderm.

Situs inversus is a very rare congenital condition in which the chest and abdominal organs are reversed or mirrored. It is usually considered a benign condition, but can also present as part of a syndrome, e.g., Kartagener syndrome.

Craniocaudal folding

  • Process: The cranial and caudal embryonic poles curl, resulting in curving of the germinal disc.
  • Result:
    • The embryo develops a C form.
      • Caudal end: tail fold
      • Cranial end: head fold
    • Constriction of the yolk sac

Lateral folding

The midgut stays connected to yolk sac remnants via the vitelline duct (omphalomesenteric duct). This duct is obliterated during the course of embryogenesis. Persistence of this duct most commonly results in Meckel diverticulum but could also cause retroumbilical cysts and fistulae.

Buccopharyngeal and cloacal membrane formation

Abnormalities of morphogenesis

Process Definition Characteristics Example
Agenesis
  • The organ is not present.
  • Primordial tissue from which the organ is derived is absent.
Aplasia
  • The organ is not present.
  • Primordial tissue from which the organ is derived is present.
Hypoplasia
  • Underdevelopment of an organ
  • Primordial tissue from which the organ is derived is present.
Disruption
  • Breakdown of a previously normal tissue or structure
  • Amniotic band syndrome
Deformation
  • Interruption of the normal development of an organ due to an extrinsic force
  • Occurs after week 8
Malformation
  • Interruption of the normal development of an organ due to an intrinsic process
  • Occurs between week 3 and week 8
Sequence
  • A single event that causes multiple abnormalities
Syndrome
  • A set of clinical features that consistently occur together
  • Commonly caused by genetic mutations (e.g., trisomy 21)

References:[2][3][4]

Differentiation of the germinal disc

Differentiation of the mesoderm

Axial mesoderm

Paraxial mesoderm

  • Location: tube-shaped area of the mesoderm surrounding the notochord
  • Components: somites
  • Process:
    • The paraxial mesoderm becomes divided into segmented round cell clusters (somites) along the neural tube.
    • Up to the beginning of the week 5, an initial 42–44 somite pairs are formed in a craniocaudal direction.
    • Degeneration of several somite pairs, resulting in a remaining 35–37 somite pairs.
    • As primitive segments, somites determine body segmentation
      • Somite segments
        • Sclerotome: medial migration of cells toward the notochord and fusion of both sclerotomes of a somite pair
        • Dermomyotome
          • Dermatome: migration toward the surface ectoderm
          • Myotome: subdivision into the dorsal epimere and ventral hypomere skeletal muscles in the lateral and anterior regions of the thorax and abdomen

Intermediate mesoderm

Lateral plate mesoderm

  • Location: lateral to the intermediate mesoderm
  • Sequence of events
    • In the second week of development, small folds develop in lateral aspect of the mesoderm.
    • These folds split horizontally to form two components.
      • Somatopleuric mesoderm: The dorsal layer that underlies the ectoderm and differentiates into the lining of the pleural, pericardial, and peritoneal cavities.
      • Splanchnopleuric mesoderm: The ventral layer that overlies the endoderm and differentiates into the visceral lining of internal organs.
    • The space between these components is called the coelom
    • The two coeloms from either side fuse at the end of the lateral folding of the embryo to form one large cavity, the intraembryonic coelom, which will differentiate into the thoracic and abdominal cavities (see “morphogenesis” above).

Mesenchyme ≠ mesoderm: The mesoderm is one of the three germinal layers that differentiates into different tissues. The mesenchyme is embryonic connective tissue that develops from the mesoderm and other germ layers.

Fate mapping

A fate map is used to determine the origin of a cell lineage, e.g., a germ layer. The following table provides an overview of the various tissue types and structures that arise from the three germ layers.

Germ layer structure Differentiated tissue/organs
Ectoderm

Neuroectoderm (neural tube)

Neural crest
Surface ectodermal placodes
Surface ectoderm
Mesoderm (intraembryonic mesoderm) Axial Prechordal
Notochord
Paraxial Sclerotome
Dermatome
Myotome
  • Skeletal muscles
    • Neck (hypomere)
    • Lateral and ventral trunk wall (hypomere)
    • Intrinsic back muscles (epimere)
    • Limbs (hypomere)
Intermediate
Lateral plate mesoderm Splanchnopleuric mesoderm
Somatopleuric mesoderm
Endoderm

References:[5]

  • 1. Sadler TW. Langman's Medical Embryology. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.
  • 2. Le T, Bhushan V, Sochat M, Chavda Y. First Aid for the USMLE Step 1 2017. McGraw-Hill Education; 2017.
  • 3. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017.
  • 4. Kadian YS, Verma A, Rattan KN, Kajal P. Vitellointestinal duct anomalies in infancy. J Neonatal Surg. 2016; 5(3): p. 30. doi: 10.21699/jns.v5i3.351.
  • 5. Hill MA. Coelomic Cavity Development. https://embryology.med.unsw.edu.au/embryology/index.php/Coelomic_Cavity_Development. Updated April 30, 2018. Accessed June 28, 2018.
last updated 11/18/2018
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