[HD 201] E01-T07-Development of Embryo_compressed

The First 8 Weeks

• This period is an exciting area for biologic research but one of the least understood
• Itis the most sensitive period to system abnormalities generated by teratogens
• Miscarriages often happen during the first trimester
• Development is divided into 23 stages by Carnegie

Carnegie Stages

• Not usually sensitive during weeks 0-2; high rate of lethality may occur
• Period of greatest sensitivity to teratogens is weeks 3-8
• Each organ also has a peak sensitivity

First Week: Ovulation to Implantation

• This week includes fertilization, cleavage, blastocyst formation, and implantation

Fertilization

• Mechanism in which the sperm joins the oocyte
• Sperm must have capacitation first for ovum fertilization
• Capacitation involves the biochemical and biophysical changes for fertilization competence
• Fertilization occurs in the ampullary region of the uterine tube

Phases of Oocyte Penetration

• Phase 1: Penetration of the corona radiata
• Phase 2: Penetration of the zona pellucida
• Phase 3: Fusion of the cell membranes of sperm and oocyte
• Out of billions of spermatozoa, only about 300 to 500 get to the oocytes
• Capacitation is a conditioning period in the female reproductive tract that lasts about 7 hours
• Capacitation destabilizes the acrosomal sperm head, enabling penetration of the outer oocyte layer

Acrosome Reaction

• Occurs after sperm capacitation
• An exocytotic event leads to the eversion of the acrosomal vesicle

Fusion of Male and Female Gametes

Letter | Description

• -- | --- A | Oocyte immediately after ovulation, showing the spindle of the second meiotic division B | Spermatozoon has penetrated the oocyte, which has finished its second meiotic division; the chromosomes of the oocyte arranged in a vesicular nucleus, the female pronucleus C | Male and female pronuclei D & E | Chromosomes become arranged on the spindle, split longitudinally, and move to opposite poles F | Two-cell stage

Cleavage

• The embryo undergoes repeated mitotic divisions after fertilization
• Results in a 2-cell, 4-cell, 8-cell, and 16-cell (morula) stages
• Each cell of a morula is a blastomere

Morula

• The 16-cell stage divides into two parts
• Inner cell mass becomes the tissues of the embryo proper
• Outer cell mass forms the trophoblast, which later contributes to the placenta
• The morula is totipotent

Blastomere

• Cells become smaller with each cleavage division, but the total cell volume doesn't change

Blastocyst Formation

• Fluid penetrates the morula as it enters the uterine cavity through the zona pellucida
• This forms a cavity as intercellular spaces become confluent, called Blastocoel
• The cavity of the blastocyst separates the blastomeres into two parts
• Occurs when morula reaches the uterine cavity and forms a blastocoel

Trophoblast

• Corresponds to the outer cell mass and forms the epithelial wall of the blastocyst
• It becomes the membrane that will protect the embryo

Embryoblast

• Corresponds to the inner cell mass
• Blastocyst implants in the endometrium along the anterior or posterior wall of the uterus
• More common in the posterior wall
• Embryonic pole of the blastocyst attaches to the uterine endometrium at the 6th or 7th day after fertilization

Location

• The location of its the inner cell mass
• Uterus is in the secretory phase during implantation

Second Week: Bilaminar Germ Disc

• Known as the "Week of Two's" because a lot of divisions happen

Extraembryonic Membrane

• Also known as Embryonic mesoderm it divides into the somatic and splanchnic layers

Chorion/Chorionic Membrane

• A collective term for extraembryonic membrane
• Composed of the cytotrophoblast and syncytiotrophoblast

Two Cavities

• Amniotic and Yolk Sac
• Epiblast has a cavity known as the amniotic cavity
• The outer cavity is the primary yolk sac. This pinches off to form the secondary yolk sac, and then the chorionic cavity

Nutrients

• The syncytiotrophoblast invades the surrounding uterine blood vessels
• This forms channels that will nourish the embryo
• The chorion or chorionic membrane is composed of the extraembryonic membrane and trophoblast

Trophoblast

• Divides into cytotrophoblast and syncytiotrophoblast

Cytotrophoblast

• This is the inner layer of mononucleated, cuboidal cells, with distinct cell boundaries
• Mitotically active and migrates to syncytiotrophoblast

Syncytiotrophoblast

• The outer multinucleated zone without distinct boundaries
• Invades the endometrial epithelium and underlying stroma
• It rapidly expands as it erodes the uterine wall

Secretes hormones

• Lactogen
• Estrogen
• Progesterone
• Human chorionic gonadotropin (hCG)

Human Chorionic Gonadotropin (hCG)

• This maintains and stimulates the corpus luteum of pregnancy to produce progesterone
• Progesterone maintains the secretory endometrium to maintain pregnancy
• Secreted by the syncytiotrophoblast as early as 8 days post-ovulation
• It is the basis of pregnancy tests

Embryoblast

• A bilaminar disc

Hypoblast

• Contains small cuboidal cells adjacent to the blastocyst cavity

Epiblast

• Contains high columnar cells and epiblast cells adjacent to the cytotrophoblast, called amnioblasts
• Cavity within is the amniotic cavity

Primitive Yolk Sac

• Trophoblast will proliferate and syncytiotrophoblast and cytotrophoblast
• The two cavities present are amniotic cavity lined by amnioblasts, and primitive yolk sac
• Flattened cells from the hypoblast form the exocoelomic membrane, which lines the inner surface of the cytotrophoblast
• Enlarged blood vessels help nourish the developing embryo

Uteroplacental Circulation

• Syncytiotrophoblasts penetrate deeper into the stroma of the uterus
• They encounter capillaries and erode the endothelial lining of these maternal capillaries
• Congested and dilated capillaries are known as sinusoids
• The syncytial lacunae become continuous with the sinusoids, and maternal blood enters the lacunar system

Provides

• nourishment to the developing embryo

Extraembryonic Mesoderm

• Extraembryonic since it is outside the developing embryo
• Divided into Splanchnic and Somatic Mesoderm
  • Splanchnic - GI Tract, etc.
  • Somatic - External Environment, Muscles, etc.
• Cells appear between the inner surface of the cytotrophoblast and the outer surface of the exocoelomic cavity
• It is derived from yolk sac cells and form a fine, loose connective tissue layer

Hypoblast

• Initially forms the exocoelomic membrane, then it will migrate again, forming the extraembryonic mesoderm
• Surrounds the yolk sac and amniotic cavity
• Initially, they have spaces: The splanchnic component (inner) and somatic component (outer)
• The connecting stalk is the future umbilical cord
• The spaces coalesce to form the chorionic cavity

Secondary Yolk Sac

• The hypoblast produces cells migrating inside the exocoelomic membrane, gradually forming the secondary yolk sac.
• The primitive yolk sac pinches off to become the secondary yolk sac.
• The extraembryonic coelom expands and forms the chorionic cavity.
• Look for chorionic cavity when doing an ultrasound for confirm viability of pregnancy during the first trimester.
• At around 3-5 weeks of gestation, if the chorionic cavity is found, pregnancy is viable.
• Three cavities should be present: Amniotic cavity, Secondary yolk sac, Chorionic cavity

Second Week of Development

• During the second week, implantation of the blastocyst is completed and blastocyst undergoes morphological changes
• This will produces a bilaminar embryonic disc, giving rise to the germ layers

Third Week: Gastrulation

• Process forming the three germ layers in the embryo: endoderm, ectoderm, and mesoderm

Germ Layers

• Epiblast is the source germ layer
• Unlike totipotent morula, are destined to differentiate into specific/specialized structures
• Used to understand tumor formation (tumors arise from germ layers)

Ectoderm Derivatives: The Outside

• Epidermis
• Hair
• Nails
• Brain
• Spinal Cord

Mesoderm Derivatives: The Insides

• Muscles
• Bones
• Connective Tissue
• Heart
• Vasculature

Endoderm Derivatives: The Innards

• GI Tract
• Respiratory Tract
• Liver and Pancreas

The Primitive Streak

• Begins when the primitive streak appears on the epiblast

Begins gastrulation

• Primitive node forms at the cephalic end, containing a slightly elevated area surrounding the primitive pit

Invagination

• Epiblast cells migrate towards the primitive streak, detach and slip beneath, forming germ layers

Formation of Germ Layers

• Epiblast cells proliferate inward and displace hypoblast cells, forming the definitive endoderm
• Remaining epiblast cells give rise to the ectoderm, and the mesoderm is formed when some epiblast cells remain in between
• Once germ layers are formed, the migrating cells from the epiblast
• Ectoderm continues to expand.

Body Axis Establishment

• Occurs early in embryogenesis, probably during morula stage
• A-P (Anterior-Posterior) and D-V (Dorsal-Ventral) axes specified before L-R (Left-Right)

The Notochord

• The notochord underlies the neural tube
• It is a signaling center for inducing the axial skeleton, and persists as the nucleus pulposus of the intervertebral disc

Formation of the Notochord

• Prenotochordal cells invaginate in the primitive node.
• They move forward cranially in the midline until the prechordal plate.
• These cells intercalate in the endoderm and proliferate.
• They eventually detach from the endoderm, forming a solid cord of cells.

Oropharyngeal and Cloacal Membranes

• The oropharyngeal membrane is at the cranial end and the cloacal membrane is formed at the caudal end
• No intervening mesoderm exists in these membranes

The Allantois

• This is a small diverticulum at the posterior end of the yolk sac, extending into the connecting stalk
• Serves as a reservoir for excretion products (urine) of the renal system in lower vertebrates
• Rudimentary in humans but may be involved in bladder development

Neurulation

• A process that marks the beginning of CNS formation, whereby the neural plate forms into a neural tube
• Steps of Neurulation:*

1. The notochord induces the formation of a thickened area of cells
2. Edges of neural plate elevate to form neural folds
3. Neural folds fuse together to form neural tube

• Fusion begins at the middle of the embryo and goes cranial and caudal with the closure of the neural tube and creates neural crest cell
• These neural crest cells contribute to the PNS by migrating ventrally and laterally

Development of Somites

• Paraxial mesoderm forms somitomeres, which give rise to mesenchyme of the head and organize into somites in occipital and caudal segments
• The somites give rise to the myotome (muscle tissue), sclerotome (cartilage and bone), and dermatome (dermis of the skin)
• **
• Somite Numbers/Approximate Age In Days*:
• The specific age numbers can be defined using Table 4. from the text.

Fourth to Eighth Weeks

• Development of the organs happens during this period, and all major external and internal structures are established
• Exposure to teratogens during this period may cause major birth defects and the time of intake determines birth defect that can be observed

Folding of Embryo

• Occurs due to rapid growth resulting in distinct head and tail formations
• Causes constriction between embryo and umbilical vesicle, resulting in cranial and caudal regions moving ventrally

Folding Planes

• Median: creates head and tail folds and moves cranial and caudal regions ventrally leading to brain growth
• Horizontal: creates right and left lateral folds

The Three Layers

• Endoderm: moves to midline, becomes primitive gut. It forms the GI tract
• Mesoderm: middle layer
• Ectoderm: Is the outermost layer

Primitive Gut Tube

• As embryonic folding continues, endoderm moves towards midline forming a primitive gut tube
• Foregut is temporarily closed by the oropharyngeal membrane (ruptures at week 4), the midgut is connected to yolk sac via the vitelline duct, and the hindgut is closed by the cloacal membrane

Folding Result

• Major body plan is established where three germ layers differentiate into specific tissues and organ systems

Other Facts

• Embryo between the amniotic cavity and secondary yolk sac
• The heart is superior to the brain
• Endoderm and ectoderm merge at oropharyngeal/cloacal membranes.
• Folding of the embryo turns flat trilaminar disc into a cylinder

Folding Directions

• Head Fold involves the ventral and caudal movements of the developing forebrain
• Septum transversum moves closer to heart,
• Tail Fold involves growth and folding which causes the connecting stalk is attached the ventral surface of the embryo
• Lateral Folding causes endoderm to form the omphalomesenteric duct, that is attached the dorsal surface of the embryo

Events in the 4th Week

• Starts at Day 24 marks the appearance of pharyngeal arches, and a heart starts to form
• On Days 26+ upper and lower limps are recognizable
• Both the Otic pits, and lens placodes also are visible

Events in the 5th Week

• Rapid development in the brain and the face
• Five areas of the brain are fully developed

Events in the 6th Week

• Is easily identifiable by limbs, and is now reflex based
• Elbows and plates are recognizable, trunks and limbs recognizable

Events in the 7th Week:

• Notches define digits

Events in the 8th Week

• Recognizable face, with eyelids, mouth and nose fully formed

Clinical Correlates

• Omphalocele:* Jarred bowels covered in membranes due to midgut herniation
• Gastroschisis:* Herniated intestinal loops where embryonic lateral body folding did not fuse
• Sacrococcygeal Teratoma:* Cells did not die.
• Thalidomide:* Interferes with limb development