MECHANISMS OF DISEASE DURING EMBRYOGENESIS

Question 1

In human development, what are the 2 main periods?

Answer 1

Two main periods: Embryonic period: Up to the end of week 8 Most of the organogenesis occurs in these first 8 weeks Fetal period: The remaining time in utero Involves growth and modelling Defects during embryogenesis result in congenital malformations

Question 2

What are the overall stages an egg goes through to develop into an adult?

Answer 2

From egg… fertilisation cleavage gastrulation neurulation and somitogenesis organogenesis …to adult

Question 3

Annotated image of a fertilised zygote 1

Question 4

Annotated image of a fertilised zygote 2 (more detail)

Question 5

Where does fertilisation occur?

Answer 5

In the fallopian duct, (ampullary region)

See image for more detail throughout

Before the development of the embryo proper, the conceptus must first implant, then generate the “germ” disc. This takes ~10 days.

Question 6

What is the process of cleavage?

Cleavage stages part 1

Answer 6

Cleavage- splitting (the zygote) without growth so must happen Quick

The 2 cell zygote divides into 4 cell zygote etc and then once it reaches 8-16 cells, it is called a morula.

Question 7

Cleavage stages part 2

Answer 7

Once the zygote has divided into 8-16 cells, it is known as a MORULA (usually day 3). It is ready to undergo its first reorganisation - called COMPACTION. During compaction, cells in the embryo sort themselves (some remain in the exterior of the embryo and some go to the interior).

The cells inside the embryo are apolar-all their sites are in contact with other sites; they don’t have any surface that is free.

The cells on the outside give rise to the TROPHECTODERM and the cells on the outside give rise to the inner cell mass.

The outside cells start pumping fluid to the inside which leads to the formation of a fluid filled cavity inside the embryo called the BLASTOCOELE.

The Blastocoele pushes the inner cell mass towards one side and gives an asymmetry to the embryo. Now it is called a BLASTOCYST.

Once it has divided into 32-64 cells, it is known as a blastocyst (usually day 4/5).

The blastocyst by now has reached the uterus and is ready to implant in the uterine wall.

The inner cell mass gives rise to 2 types of cells:

cells on the edge(dark purple in a line in the image) between the inner cell mass and blastocoele and the group of inner cells that do not come into contact with the blastocoele. This gives rise to the HYPOBLAST and the EPIBLAST.

So now you can identify the bilaminar germ disc.

Epiblast-coming from inner cell mass and hypoblast on the outer (dark purple), epiblast seen on next slide as beige.

Question 8

Cleavage Stages part 3

Answer 8

The EPIBLAST cells arrange themselves so that they give rise to another cavity which will become the amniotic cavity.

The embryo is now ready to undergo the second main reorganisation- GASTRULATION.

Question 9

What is gastrulation?

What occurs in the Gastrulation stage?

Answer 9

Gastrulation is the process where the bilaminar embryonic disc (consisting of the hypoblast and epiblast) undergoes reorganisation to form a trilaminar disc. (3 primary germ layers)

Gastrulation leads to the formation of 3 layers of cells (from 2 layers).

Cells in the epipblast through a primitive groove will displace cells in the hypoblast, forming the mesoderm and endoderm,

(Hypoblast (primitive endoderm) is displaced by involuting cells that become definitive endoderm, and mesoderm)- words from the slide so likely more correct.

Then gives rise to ECTODERM. So now there are all 3 layers and ready for NEURULATION.

Summary from video of Gastrulation:

• The first cells to invaginate through the primitive groove form the definitive endoderm (the endoderm is responsible for the formation of the GI tract
• The remaining cells of the epiblast are called the ectoderm
• Cells that remain in the space between the definitive endoderm and definitive ectoderm form a layer called the mesoderm.

Question 10

What occurs in neurulation?

Answer 10

The notochordal process is source of neural inducers.

The primitive streak moves up and then comes back down, laying down the notochord for formation.

NOTOCHORD- rod of cells which secrete various extracellular molecules that will instruct the ectoderm to become neural tissue and neural plate is established.

As the primitive streak regresses, the notochord is extended posteriorly and instructs neural plate formation (now at 21 days).

Neural folds then meet and fuse to create a neural tube

Question 11

Neurulation First steps overview slide

Question 12

Neurulation part 2 (what happens days 20-22?)

Answer 12

Cell reorganisation also occurs too here.

Mesodermal cells start to become segmented in tissue blocks called SOMITES. (precursors of bones and muscles)

Neurulation is concomitant with other form-shaping (morphogenetic) processes, particularly gut formation and body folding (“silk purse” model).

Folding leads to the formation of the umbilical cord.

Question 13

What occurs in Organogenesis?

Answer 13

•Differentiation of somitic derivatives

–bones, muscles, tendons

•Development of sensory organs

–ears, eyes, olfactory pits

•Limb formation

–forelimbs first, hindlimbs next

–establishment of pattern in the limbs: proximodistal, anterior-posterior, dorsal-ventral

•Formation of face structures

–jaws, nose, tongue, palate

•Formation of genital structures

Question 14

Classification of causes of disease(?)

Answer 14

Single gene mutations: refers to the cases when mutation in one particular gene will be enough to display a characteristic defect.

Chromosomal anomalies: in some cases, rather than single mutations, whole chromosomal rearrangements are responsible for a disease. The most obvious examples are chromosomal trisomies, such as trisomy of chromosome 21, leading to Down syndrome.

Polygenic disorders: refers to cases where it is not just one gene affected, but several different genes simultaneously affected, what causes the disease.

Environmental factors: refers to the deleterious influence of the environment on a particular process. These can be very diverse: diet, infection, toxic compounds.

Question 15

Summary of the above lecture

Answer 15

Human embryonic development is a very complex process, controlled by networks of genes acting together.

Defects in gene function during this process will result in defective embryonic development.

Some genes are needed at several different stages of embryonic development, or in several organs. Alterations in the function of such genes will result in complex phenotypes in a variety of tissues. These are called syndromic diseases.

Embryonic development can also be perturbed by environmental insults, maternal diet deficiencies or infections during pregnancies.

Often, it is a combination of genetic and environmental causes what results in congenital disease.

Identifying the relative contribution of these factors is a challenging and often very difficult process.

Question 16

What periods are human development divided into?

Answer 16

Human development can be divided into two stages:
Embryonic period
• Up to the end of week 8
• Most of the organogenesis occurs in these first 8 weeks
Fetal period
• The remaining time in utero
• Involves growth and modelling, refinement or organs and tissues

Question 17

What are the mechanisms of development during embryogenesis from the egg?

Answer 17

From Egg:
• Fertilisation
• Cleavage
• Gastrulation
• Neurulation and somitogenesis
• Organogenesis
• To give rise to adult form

Question 18

What can be seen in the fertilised zygote?

Answer 18

• We can see the pronuclei
• It is covered by zona pellucida
• Inside are the polar bodies – remaining genetic material that has been extruded.

Question 19

What happens when the egg is fertilised?

Answer 19

1. Fertilisation occurs in the fallopian ducts
2. It takes 10 days for the fertilised egg to get to the uterus, during this time the zygot will undergo cleavages to form the morula
3. Then the re-organisation of these cells occurs to give rise to the blastocyte

Question 20

Describe the cleavage stage?

Answer 20

• The fertilised zygote will form a 2 cell zygote and then a 4 cell zygote and so on
• Once is gets to 8-16 cells it is called a morula which is ready to undergo its first re-organisation known as compaction
• During compaction, cells in the embryo sort themselves, some remain in the exterior and some remain in the interior of the embryo.
• The outside cells will form cell contacts with the neighbouring cells. the basal lateral surface is in contact with the external environment
• All cells inside the embryo are apolar, all their sites are in contact with other cells and they don’t have any cell surface that is free
• The cells in the outside give rise to the tropfectedor and the cells in the inside give rise to the inner cell mass.
• The outside cells start pumping fluid into the embryo forming a fluid filled cavity inside called the blastocoele, this pushes the inner cell mass to one side and starts giving an asymmetry – now known as a blastocyst (32-64 cells).
• The blastocyst has reached the uterus and is ready to implant into the uterus and the inner cell mas gives rise to edge cells and the exterior cells giving rise to the hypoblast and epiblast.
• As the embryo full fully implants we can identify the bilaminar germ disk.
• There epiblast cells also give rise to the amniotic cavity

Question 21

Describe gastrulation

Answer 21

1. Gastrulation gives rise to form three layers of cells from the germ disk
2. At one end from the bilaminar germ disk a groove forms on the epiblast: primitive groove
3. Cells form the epiblast ingress through the groove and spread beneath the epiblast
4. This displaces the hypoblast and forms the endoderm and mesoderm giving rise to the ectoderm.

Question 22

Describe the start of neurulation

Answer 22

Ectoderm
• Specification of the central nervous system.
• The primitive streak will then start to ingress leaving structure behind such as the notochord. The notochord is a group of cells that secretes several extracellular molecules that tells the ectoderm to become neural tissue. The neural plate then becomes established.
• As the primitive streak regress the notochord gets extended posteriorly which instructs the overlying ectoderm to form the neural plate so we end up with the neural plate on top of the notochord

Question 23

How does the neural plate give rise to form a tube called the neural tube?

Answer 23

The neural plate then gives rise to form a tube called the neural tube
• The neural plate starts to fold, and the edges come together
• This forms a tube underneath the ectoderm
• Closure of the neural tube doesn’t occur all at once. It starts as the between the hindbrain and spinal cord and progresses as a zip anteriorly and posteriorly to form a tube

Question 24

What do the mesoderm cells form?

Answer 24

• The mesodermal cells become segmented called somites

* These somites give rise to the muscle, bones and tendons

Question 25

How is neurulation is concomitant with other form-shaping (morphogenetic) processes, particularly gut formation and body folding (“silk purse” model)?

Answer 25

• The mesoderm and endoderm will give rise to the organs. So, they need to be enclosed. So the embryo fold on itself, known as body folding
• The septum and heart move form the margin to the centre
• The yolk sac, allantois and stalk make the umbilical cord
• Prochordal and cloacal plates delimit the gut tube

Question 26

What are the subsets of Organogenesis?

Answer 26

• Differentiation of somitic derivatives
o bones, muscles, tendons
• Development of sensory organs
o ears, eyes, olfactory pits
• Limb formation
o forelimbs first, hindlimbs next
o establishment of pattern in the limbs: proximodistal, anterior-posterior, dorsal-ventral
• Formation of face structures
o jaws, nose, tongue, palate
• Formation of genital structures

Question 27

What are the desirable characteristics of a model organism

Answer 27

• Relevance/ representative
• Accessibility/ availability
• Experimental manipulation
• Genetics
• Cost/space

Question 28

Define single gene mutations

Answer 28

Single gene mutations: refers to the cases when mutation in one particular gene will be enough to display a characteristic defect.

Question 29

Define chromosomal abnormalities

Answer 29

Chromosomal anomalies: in some cases, rather than single mutations, whole chromosomal rearrangements are responsible for a disease. The most obvious examples are chromosomal trisomies, such as trisomy of chromosome 21, leading to Down syndrome.

Question 30

Define polygenic disorders

Answer 30

Polygenic disorders: refers to cases where it is not just one gene affected, but several different genes simultaneously affected, what causes the disease.

Question 31

Define Environmental factors

Answer 31

Environmental factors: refers to the deleterious influence of the environment on a particular process. These can be very diverse: diet, infection, toxic compounds. Can you think of any specific examples?