15. Embryonic Development Flashcards
(213 cards)
1
Q
Give some reasons for studying embryology?
A
- Model system for cell/molecular biology
- Understanding congential defects
- Model for regenerative medicine
2
Q
What are some model systems used in embryology?
A
- Xenopus (frog)
- Chick
- Mouse
- C elegans
- Zebrafish
3
Q
Give an example of a gene that is conserved between species.
A
- Pax6 is conserved in humans, mice, zebrafish and drosophilia
- A mutation in the Pax6 gene results in eyeball abnormalities in all of these species
4
Q
Name some advantages of the fly as a model system for embryology.
A
- Cheap
- Short lifespan
- Easy to manipulate
5
Q
Name some advantages of the mouse as a model system for embryology.
A
- Foremost mammalian model
- Short gestation period
- Highly similar development to humans
6
Q
Name some advantages of C elegans as a model system for embryology.
A
- Cheap
- Have fixed no. of cells -> Exact development + position of each cell has been mapped
7
Q
Name some advantages of the chick as a model system for embryology.
A
- Accessible -> Grows in eggs
8
Q
Name some of the important aspects of development.
A
- Cell differentiation
- Patterning
- Induction
- EMT and MET (epithelial to mesenchymal transitions and mesenchymal to epithelial transitions)
- Morphogenesis
- Cell death
9
Q
Are signalling pathways ever reused in the development?
A
Yes, the same signalling pathways appear in many places in the human body.
10
Q
What are the main important stages in embryonic development?
A
- Fertilisation (Day 0)
- Pre-embyronic stage (Day 0)
- Implantation
- Bilaminar germ disc
- Embryonic period (3rd week)
- Gastrulation + Axis formation
- Neurulation
- Embryonic folding
- Somitogenesis
- Limb bud formation
- Organogenesis
- Fetal period (8th week)
- Growth
- Maturation
- Birth
11
Q
What is the product of fertilisation?
A
Diploid zygote
12
Q
Define fertilisation.
A
The joining of an egg and sperm to produce a diploid zygote.
13
Q
Describe the process of fertilisation.
A
- Occurs in ampullary region of oviduct (the far end, near the ovary) – Note: Oviduct = Fallopian tube
- In order to fertilise oocyte, spermatozoa need:
- Removal of glycoprotein coat (capacitation) -> This is calcium dependent
- Binding to zona pellucida -> Activates acrosome reaction, where acrosome (a Golgi-derived organelle in the head of the spermatozoon) releases enzymes to break through the zona pellucida
- As spermatozoon enters the zona pellucida, the membrane of the spermatozoon fuses with the membrane of the oocyte, releasing the spermatozoon nucleus into the oocyte
- At the same time, the cortical granules of the oocyte release their contents, making the zona pellucida impenetrable to other spermatozoa
- Entry of the spermatozoon nucleus stimulates the oocyte to complete the second meiotic division (meiosis has not yet been completed) -> It is now called a definitive oocyte and the two nuclei are called the female pronucleus and male pronucleus (the name for the nucleus during fertilisation)
- Since it has been fertilised, the definitive oocyte can also be called the zygote
- The two pronuclei approach each other and duplicate their DNA, ready for the first mitotic division
- Pronuclear membranes break down and the chromosomes line up for metaphase
- First cell division takes place
14
Q
What percentage of sperm reach the cervix and what happens to them there?
A
- About 1%
- Ovulation induces them to move further into the oviduct
15
Q
What are the technical names for the sperm and egg?
A
- Sperm = Spermatozoon (pl. spermatozoa)
- Egg = Oocyte
16
Q
Where does fertilisation occur?
A
Ampullary region of oviduct (a.k.a. fallopian tube)
(far end, near the ovary)
17
Q
Draw out the path of spermatozoa to the oocyte.
A
18
Q
What two things must happen in order for the spermatozoon to enter the oocyte?
A
- Removal of glycoprotein coat (capacitation) -> This is calcium dependent
- Binding to zona pellucida -> Activates acrosome reaction, where acrosome (a Golgi-derived organelle in the head of the spermatozoon) releases enzymes to break through the zona pellucida
19
Q
What prevents multiple spermatozoa fertilising the oocyte?
A
Cortical granules (just inside the plasma membrane) release their contents, making the zona pellucida impenetrable.
20
Q
Describe the process of meiosis involved in generating the female pronucleus.
A
- The process of meiosis is halted just before the second meiotic division
- When the male pronucleus enters the oocyte, this triggers the second meiotic division -> This creates the female pronucleus
21
Q
How is the first mitotic division different to normal mitotic divisions?
A
The DNA duplication occurs before the male and female pronuclei even fuse.
22
Q
What are pronuclei?
A
The nuclei of the gametes during the process of fertilisation.
23
Q
Draw a diagram of an oocyte and spermatozoon.
A
24
Q
What is a zygote?
A
The union of the sperm cell and the egg cell. Also known as a fertilized ovum.
25
What is cleavage?
A series of mitotic divisions without cell growth.
26
Describe the process of cleavage.
* Cleavage is a series of mitotic divisions without cell growth
* All of the cells during cleavage are called blastomeres
* Cleavage occurs with all of the cells still within the zona pellucida, while travelling down the oviduct
* At the 8 to 16 cell stage, outer cells begin to form tight junctions with each other, which is called compaction -\> This leads to the morula structure
* Morula (from the Latin for mulberry) -\> 16 to 32 cells
* Inner cell mass (ICM) (a.k.a. embryoblast) -\> On the inside of the morula -\> Loses totipotency so can only form embryo
* Trophoblast -\> On the outside of the morula -\> Keeps totipotency and goes on to form placenta
* Blastocyst (not to be confused with blastula: blastocyst is what a blastula is called in mammals)
* Blastocystic cavity (a.k.a. blastocoel) -\> Formed by the absorption of fluid
* Inner cell mass (ICM) (a.k.a. embryoblast) -\> Is forced to one side of the cavity as a compact mass
* Trophoblast -\> Is now a single-layered epithelium around the outside
* The zona pellucida degenerates and the blastocyst is able to hatch out
27
What are the cells in a cleaving morula or blastocyst called?
Blastomeres
28
What is compaction?
In the 8 to 16 cell phase of cleavage, outer cells start to form tight junctions with each other.
29
What are the different structures seen during cleavage? Draw diagrams.
* Morula (from the Latin for mulberry) -\> 16 to 32 cells
* Inner cell mass (ICM) (a.k.a. embryoblast) -\> On the inside of the morula -\> Loses totipotency so can only form embryo
* Trophoblast -\> On the outside of the morula -\> Keeps totipotency and goes on to form placenta
* Blastocyst (not to be confused with blastula: blastocyst is what a blastula is called in mammals)
* Blastocystic cavity (a.k.a. blastocoel) -\> Formed by the absorption of fluid
* Inner cell mass (ICM) (a.k.a. embryoblast) -\> Is forced to one side of the cavity as a compact mass
* Trophoblast -\> Is now a single-layered epithelium around the outside
30
Clinical relevance: Describe the different types of twins and how they arise.
* Dizygotic twins -\> Two seperate blastocysts, which form embryos that may have a fused placenta but do not share blood supply
* Monozygotic twins I -\> ICM splits, which form embryos that have a common placenta and sometimes share a blood supply
* Monozygotic twins II -\> Splitting occurs anywhere between two-cell to morula stage, which form embryos that may share placenta but do not share blood supply
31
Give some examples of the clinical relevance of fertilistaion and cleavage.
* Twins
* IVF
* Cloning
* Embryonic stem cells
32
When does the developing embryo lose the zona pellucida?
* After it is a blastocyst
* Blastocyst 'hatches' from the disintegrating zona pellucida around day 5
* This allows for implantation
33
Describe the process of IVF.
* Hormonal stimulation of mature oocyte formation produces several mature follicles
* Collection of oocytes
* Placement in Petri dish and fertilisation in vitro
* Cleavage of zygotes in medium until 4 to 8 cell stage is reached
* Transfer to up to 5 embryos into uterine cavity using a catheter
34
During implantation, what does the blastocyst adhere to?
Endometrium (uterus wall)
35
Describe the process of implantation. Draw diagrams.
* Morula reaches uterus by day 3/4 of development
* Blastocyst hatches from zona pellucida and adheres to endometrium lining (uterus wall)
* This triggers decidual reaction: endometrial stroma (connective tissue) responds to blastocyst and progesterone from the corpus luteum and turns into decidual cells (secretory cells) -\> These secrete lots of glycogen and mucus for immunological protection
* The uterine wall becomes more vascularised and oedematous (swollen)
* Trophoblast near the uterus begins to grow into the uterine wall, forming a syncytiotrophoblast that starts pulling the blastocyst into the uterine wall
36
What is the decidual reaction?
It is part of the implantation process:
* The stroma (connective tissue) in the endometrium responds to binding of the blastocyst as well as progesterone from the corpus luteum
* Stroma cells differentiate into decidual cells (secretory cells) -\> These secrete lots of glycogen and mucus for immunological protection
37
Give some clinical relevance of implantation.
Ectopic pregnancy:
* When a blastocyst implants outside the uterus, for example in the pericardial cavity or on the surface of the oviduct, the epithelium coming in contact with the blastocyst will still react, becoming more vascularised
* This allows the blastocyst to survive outside the uterus and start to develop, but it will not reach term
* This may be threatening to the mother due to, for example, haemorrhage
38
What does the trophoblast do during implantation?
* At one pole of the trophoblast, the syncytiotrophoblast and cytotrophoblast form from trophoblast cells
* Syncytiotrophoblast cells are the cells that initially invade the endometrium, drawing the blastocyst into the uterine wall -\> Ruptures capillaries so creating an interface between maternal blood and embryonic fluid for passive transfer. Also secretes a lot of hCG to maintain corpus luteum
* Cytotrophoblast cells line the inside of the syncytiotrophoblast and will eventually form the foetal portion of the placenta
39
What things trigger the decidual reaction?
* Progesterone from the corpus luteum
* HcG from the synctiotrophoblast assists with this by maintaining the corpus luteum
40
What are hydratidiform moles and what are the two main types? [EXTRA]
* Growth of an abnormal fertilized egg or an overgrowth of tissue from the placenta
* Embryos derived from two male haploid genomes (androgenotes) give rise to largely placental tissue
* Embryos derived from two female pronuclei (gynogenotes) give rise to largely embryonic tissue
41
What is the first structure that is formed after implantation?
Bilaminar germ disc
42
What does the bilaminar germ disc form from?
Inner cell mass (ICM)
43
What are the two layers of the bilaminar germ disc?
* Hypoblast
* Epiblast
44
What are the two cavities that surround the bilaminar germ disc?
* Amniotic cavity
* Yolk sac
45
Which layer of the bilaminar germ disc gives rise to the amnion and which gives rise to the yolk sac?
* Epiblast -\> Amnion
* Hypoblast -\> Yolk sac
46
What is the amnion and amniotic cavity?
* The amnion is a membrane that closely covers the embryo when first formed.
* It fills with the amniotic fluid which causes the amnion to expand and become the amniotic sac which serves to provide a protective environment for the developing embryo or fetus.
47
Which cell group forms the placenta?
Trophoblast
48
Describe the formation of the amniotic cavity and yolk sac.
Amniotic cavity:
* Develops between the epiblast and cytotrophoblast
* Cells from the epiblast form amnioblasts that line the cavity -\> This is called the amnion
* The amniotic cavity will eventually engulf the entire embryo
Yolk sac:
* Cells from the hypoblast migrate out in the two waves
* Wave 1: Forms the primary yolk sac
* The exocoelomic (Heuser's membrane) that lines the primary yolk sac is formed by the migrating hypoblast cells
* Wave 2: transforms the primary into the secondary yolk sac
49
After initial implantation by the synctiotrophoblast and cytotropohblast, how does the embryo implant further?
* The emrbyo keeps embedding further into the endometrium until the cytotrophoblast surrounds the embryo and a coagulation plug is formed
* Vacuoles in the synctiotrophoblast cells fuse to give lacunae
50
What are the extraembryonic mesoderm and how does it form?
* The extraembryonic mesoderm is the layer of mesoderm that forms just inside of the cytotrophoblast (between the cytotrophoblast and amnion + lining of primitive yolk sac)
* It is formed by the migration of cells from the edges of hypoblast and epiblast
51
What are the chorionic cavity and how does it form?
* Chorionic cavity = Extraembryonic coelom
* It is the cavity that forms within the extraembryonic mesoderm, between the cytotrophoblast and the embryo
52
Describe how the secondary yolk sac forms from the primary yolk sac. What structures form alongside this?
* The trophoblast grows much faster than the bilaminar disc
* This gives rise to the chorionic cavity and secondary yolk sac
* The connecting stalk left behind forms the umbilical cord
53
What happens to the lacunae in the synctiotrophoblast?
They fill with blood due to the decidual reaction prompting greater vascularity.
54
Summarise the main events just after implantation, up to the formation of the secondary yolk sac.
Implantation:
* Morula reaches uterus by day 3/4 of development
* Blastocyst hatches from zona pellucida and adheres to endometrium lining (uterus wall)
* At one pole of the trophoblast, the syncytiotrophoblast and cytotrophoblast form from trophoblast cells:
* Syncytiotrophoblast cells are the cells that initially invade the endometrium, drawing the blastocyst into the uterine wall -\> Ruptures capillaries so creating an interface between maternal blood and embryonic fluid for passive transfer
* Cytotrophoblast cells line the inside of the syncytiotrophoblast and will eventually form the foetal portion of the placenta
* The decidual reaction is triggered by progesterone from the corpus luteum and hCG from the synctiotrophoblast assists with this by maintaining the corpus luteum
* Decidual reaction: Endometrial stroma (connective tissue) turns into decidual cells (secretory cells) -\> These secrete lots of glycogen and mucus for immunological protection
* The uterine wall becomes more vascularised and oedematous (swollen)
* Bilaminar germ disc forms from the ICM -\> The two layers are the hypoblast and epiblast
Amniotic cavity forms from the epiblast:
* Develops between the epiblast and cytotrophoblast
* Cells from the epiblast form amnioblasts that line the cavity -\> This is called the amnion
* The amniotic cavity will eventually engulf the entire embryo
Yolk sac forms from the hypoblast:
* Cells from the hypoblast migrate out in the two waves
* Wave 1: Forms the primary yolk sac
* The exocoelomic (Heuser's membrane) that lines the primary yolk sac is formed by the migrating hypoblast cells
* Wave 2: transforms the primary into the secondary yolk sac
Later implantation:
* The embryo keeps embedding further into the endometrium until the cytotrophoblast surrounds the embryo and a coagulation plug is formed
* Vacuoles in the synctiotrophoblast cells fuse to give lacunae -\> These fill with blood due to increased vascularity
* The extraembryonic mesoderm is the layer of mesoderm that forms just inside of the cytotrophoblast (between the cytotrophoblast and amnion + lining of primitive yolk sac) -\> It is formed by the migration of cells from the edges of hypoblast and epiblast
* The trophoblast grows much faster than the bilaminar disc
* This gives rise to the chorionic cavity and secondary yolk sac
* The connecting stalk left behind forms the umbilical cord
55
Compare the body axes in the adult and embryo.
56
What does the epiblast give rise to eventually?
All embryonic tissues.
57
What is gastrulation?
A complex series of movements during which the three germ layers establish their appropriate topological positions and the basic body plan emerges.
58
What are germ layers?
An operational definition describing three cell layers/types that give rise to different organ systems in the body.
59
What germ layer are mesenchymal cells derived from?
* Mesenchymal cells can derive from any germ layer
* They form a loosely organised tissue, which frequently differentiates subsequently into specific cell types (eg. mesenchymal cells of the sclerotome will form the vertebral column); mesenchymal cells in skull development
60
What are the 3 definitive germ layers?
* Ectoderm (on the side of the amniotic cavity)
* Mesoderm
* Endoderm
61
Describe the process of gastrulation.
* Gastrulation begins with the formation of a primitive streak, which is a shallow marked line along the epiblast.
* This begins at what is now defined as the caudal end of the epiblast and runs along the midline.
* At the cranial (or rostral) end of the streak, a circular region called the primitive node forms, which contains a depression called the primitive pit.
* This depression continues down the primitive streak, forming a long, linear primitive groove. The primitive groove along with the primitive pit mark sites to which epiblast cells migrate and travel towards the mesoderm (a process known as ingression), beginning the process of creating a trilaminar embryonic disc.
* Endoderm is formed by the invasion of the hypoblast. Cells leaving the primitive streak displace the hypoblast cells and gradually form the endoderm.
* Mesoderm forms when the epiblast cells migrate laterally or cranially after passing through the primitive groove, before they reach the endoderm. This forms a layer of cells between the endoderm and the epiblast. A
* Ectoderm is essentially what remains of the epiblast after gastrulation is complete.
62
What gastrulation begin with?
Begins with the formation of a primitive streak, which is a shallow marked line along the epiblast.
63
Describe how gastrulation defines the body axis.
* Gastrulation begins with the formation of a primitive streak, which is a shallow marked line along the epiblast.
* This occurs at what is now defined as the caudal end (relating to the “tail) of the epiblast.
* Aside from determining the cranial-caudal axis, the streak is defined as running as medially as possible, so the medial-lateral direction is perpendicular to this.
* Right and left are also defined when looking down at the ectoderm from the amniotic fluid, when the caudal end is closest to the viewer.
64
What does the primitive node act as?
An organiser.
65
What determines what an ingressing cell passing through the primitive streak becomes?
The time at which it passes past the primitive node and through the primitive streak.
66
What are some defects in primitive node and streak activity?
67
What transition do cells undergo when they ingress during gastrulation?
EMT (epithelial-to-mesenchymal transition)
68
Which direction does the primitive streak move in during gastrulation?
Caudally
69
What are the two broad categories of structure that the ectoderm goes on to form?
70
What is neurulation?
The formation of the neural tube.
71
Describe neurulation.
* The notochord (in the mesoderm) along the midline induces the ectoderm above it to differentiate into the neural plate
* The neural plate folds downwards so that the two sides of it fuse
* This produces a tube called the neural tube
* The cells just above it are called the neural crest
72
What transition do neural crest cells undergo?
EMT (epithelial to mesenchymal transition)
73
What is the neural plate?
The area of ectoderm along the midline that goes of to form the neural tube.
74
What induces neurulation?
Notochord (in the mesoderm just below the neural plate)
75
What are two examples of neural tube closure defects?
76
In summary, what does the nervous system form from? [IMPORTANT]
Neuroectoderm
77
What are the derivatives of the neural tube?
CNS
78
Summarise the derivatives of the neural crest. [IMPORTANT]
* PNS
* Dorsal root ganglia
* Autonomic ganglia
* Cranial nerve ganglia
* Enteric nervous system
* Schwann cells
* Skin -\> Melanocyte
* Cranial bones
* Eyes
79
Give an example of a condition caused by failure of neural crest cell migration.
80
In general, summarise the different types of tissue that mesoderm goes on to form.
* Muscle
* Connective tissue
* Blood, etc.
81
What are the different types of mesoderm?
* Prechordal (head)
* Axial (notochord)
* Paraxial (somites)
* Intermediate
* Lateral plate
82
What is another name for the notochord?
Axial mesoderm
83
What are some roles of the notochord?
* Induces the neural plate (and therefore neural tube)
* Patterns the neural tube in the dorso-ventral axis
* Forms primitive axis around which axial skeleton is laid down
84
What does the notochord go on to form? [IMPORTANT]
Nucleus pulposus of intervertebral discs
85
How are the neural tube and associated structures patterned in the craniocaudal axis?
Check this -\> Thought it was Hox genes but it might be Shh
86
How is the notochord patterned in the dorsoventral axis?
* Shh, initially from the notochord, but subsequently from the most ventral cells of neural tube, forms a concentration gradient across neural tube
* It induces different ventral fates in neural tube, while BMPs regulate dorsal fates
87
What is another name for the paraxial mesoderm?
Somites
88
Describe somitogenesis.
* Somites form in the paraxial mesoderm (on either side of the notochord)
* They form in a craniocaudal direction, at a rate of approximately 3 a day
* At end of 5th week → 4 occipital, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral and 8-12 coccygeal (first occipital and last 5 coccygeal somites lost later)
89
How many somites form?
37 -\> But the first occipital and last 5 coccygeal are lost at a later point
90
What parts are somites divided into and what is this induced by?
Under influence from the lateral plate mesoderm, ectoderm and neural tube, somites divide into 3 different populations:
* Sclerotome
* Dermamyotome, which divides further into:
* Dermatome
* Myotome
91
What does the sclerotome (of somites) give rise to?
Vertebrae and ribcage
92
How does the sclerotome give rise to the vertebrae and ribcage?
The medioventral portion of each somite migrates and the cells surround the notochord.
93
Describe how the somites lead to segmentation of the peripheral nervous system.
94
Describe the positions of the sclerotome, dermatome and myotome within the somite.
* Sclerotome -\> Medioventral
* Myotome -\> Dorsomedial and dorsolateral
* Dermatome -\> Rest of somite
95
Describe spina bifida.
96
What are the derivatives of the myotome of the somites?
Skeletal muscle
97
Describe how the myotome gives rise to different skeletal muscles.
* Dorsolateral cells (hypaxial myotome) in the somite migrate ventrally
* Gives rise to limb and body wall muscles
* Dorsomedial cells (epaxial myotome)
* Gives rise to back muscles
98
What are the derivatives of the dermatome of the somites?
Dermis of skin (e.g. fibroblasts) and subcutaneous fat
99
What are the derivatives of the intermediate mesoderm?
Urogenital system
100
What are the derivatives of the lateral plate mesoderm?
* Parietal → Lateral and ventral body wall (i.e. dermis & limb buds)
* Visceral wall of gut
101
What are the derivatives of the endoderm?
* Digestive
* Epithelium of digestive tract
* Digestive organs -\> Stomach, Intestine, Liver, Gall bladder, Pancreas
* Respiratory system
* Thyroid and parathyroid glands
* Urothelial cells
102
Draw a diagram to show the signalling centres involved in patterning the different parts of a somite.
103
Summarise the derivatives of ectoderm.
Surface mesoderm:
* Skin (Note: Epidermis) -\> Keratinocytes
Neural crest
* PNS -\> Neuron, Schwann cell
* Skin -\> Melanocyte
* Cranial bones
* Eyes
Neural tube:
* CNS -\> Neuron
104
Summarise the derivatives of mesoderm.
Notochord:
* Nucleus pulposus of intervertebral discs
Paraxial mesoderm (somites):
* Dermatome -\> Dermis of skin (e.g. fibroblasts) and subcutaneous fat
* Sclerotome -\> Vertebrae and ribcage
* Myotome -\> Skeletal muscle cells
Intermediate mesoderm:
* Urinary system
* Reproductive system
Lateral plate mesoderm (involved in limb bud formation):
* Circulatory system (including heart) -\> CHECK?
* Lateral and ventral body wall (i.e. dermis & limb buds)
* Visceral wall of gut
105
Summarise the derivatives of endoderm.
* Digestive:
* Epithelium of digestive tract
* Digestive organs -\> Stomach, Intestine, Liver, Gall bladder, Pancreas
* Respiratory system
* Thyroid and parathyroid glands
* Urothelial cells
106
What does body patterning rely on?
* Requires establishment of one or more spatially localised signalling centres
* A limited repertoire of signalling molecules is used and reused in development and in evolution
107
What are the limbs a good model of patterning?
* Unlike many organs, they are dispensible
* Defects are relatively easy to recognise
108
When does development of the limb bud happen?
Between weeks 4 and 8
109
Which limbs develop first?
The upper limbs develop 1-2 days before the lower limbs.
110
What are the main types of limb development abnormalities? [EXTRA?]
* Reduction defects, eg., amelia, meromelia (phocomelia)
* Duplication defects, eg., polydactyly
* Malformation (dysplasia), eg., syndactyly
111
At what heights do the upper and lower limb buds develop?
* Upper limbs: C5 to T1 level
* Lower limbs: L1 to L5 level
112
What is a limb bud?
* A collection of proliferating mesenchymal cells (the progress zone) from the lateral plate mesoderm that begins to bulge outwards on the overlying ectoderm.
* It is the structure that begins limb formation.
113
Describe the different signalling molecules involved in limb bud formation and how the limb buds form at the correct axial levels.
* There is a craniocaudal Hox gradient.
* Specific Hox gene expression leads to the release of T-box transcription factors.
* These stimulate FGF10 (signalling protein) production in the lateral plate mesoderm.
* This in turn induces the ectoderm to thicken into an apical ectodermal ridge (AER).
* The AER stimulates the continued mesenchymal proliferation (positive feedback) by producing FGF8 and FGF4.
114
Draw the structure of a limb bud, including the axes.
115
What is Sprengel's syndrome? [EXTRA?]
In Sprengel’s syndrome, changes in Hox gene expression can result in more rostral upper limbs, since the induction of limb bud formation occurs at a different level.
116
What determines the identity of the upper and lower limbs?
* Upper limb -\> Tbx4 expression
* Lower limb -\> Tbx5 expression
117
Describe how limb outgrowth and patterning occurs in the proximodistal axis.
Patterning:
* The AER induces the proximodistal axis, where the later a cell is in contact with the AER, the more distal the limb structure that it forms.
Outgrowth:
* Specific Hox gene expression leads to the release of T-box transcription factors.
* These stimulate FGF10 (signalling protein) production in the lateral plate mesoderm.
* This in turn induces the ectoderm to thicken into an apical ectodermal ridge (AER).
* The AER stimulates the continued mesenchymal proliferation (positive feedback) by producing FGF8 and FGF4.
118
Describe how limb patterning occurs in the anteroposterior (craniocaudal) axis.
* The zone of polarising activity (ZPA) is a region of mesenchymal cells on the posterior side of the limbs.
* It patterns the structures along the anteroposterior axis, such as the order of the digits, by sonic hedgehog (Shh) gradients, which affect the transcription of Hox genes.
119
What is it important to remember about the anteroposterior axis in embryology?
It is the same as the craniocaudal axis.
120
Describe how limb patterning occurs in the dorsoventral axis.
The dorsoventral signalling centre is in the dorsal ectoderm, which functions by Wnt7a signalling that induces transcription factor activity in the dorsal mesenchyme (especially activity of Lmx1).
121
What is the AER and what does it do?
* Apical ectodermal ridge
* It is a thickening of the ectoderm on the distal side of the limb bud
* It induces growth in underlying mesenchyme (via FGF4 and FGF8), while the mesenchyme signals back to AER (via FGF10) -\> This is positive feedback so limb growth occurs
122
When does the AER form?
In 5th week
123
What is the result of removal of the AER experimentally?
124
What are amelia, meromelia and phocomelia
and what causes them?
125
What is the progress zone in a limb bud?
* The progress zone is a layer of mesodermal cells immediately beneath the apical ectodermal ridge in the developing limb bud.
* There is a positive feedback loop between the AER and progress zone.
126
What is the ZPA and what does it do?
* Zone of polarizing activity
* An area of mesenchyme at the posterior (caudal) part of the limb bud.
* Contains signals that pattern the anterior/posterior axis.
127
What is the significance of the dorsal ectoderm in the limb bud?
It is the structure that patterns the dorsoventral axis.
128
Draw a diagram to show how Shh acts as the morphogen of the ZPA.
129
Draw cleft foot and hand and how it occurs.
130
How do the digits form during limb development?
* A combination of apoptosis and digit growth
* Cutaneous syndactyly = most common syndactyly due to failure of this process
131
Describe the process of dorsoventral patterning in limb formation in more detail.
132
Experimentally, what happens if you graft an Shh-secreting pellet onto the anterior side of a limb bud?
Can result in mirror-image duplications.
133
How does limb musculature develop and when?
In the 5th week, mesoderm from the somites (myotome) migrates to the limb buds and forms dorsal and ventral muscle mass, responsible for (mostly) the extensor and flexor muscle respectively.
134
Describe how the bones of limbs develop and when.
* In the 6th week, the mesenchymal core of the limb buds starts forming hyaline cartilage models, the complete set of which is formed by the week’s end.
* By week 12, ossification begins, so that the diaphysis of long bones is fully ossified by birth.
135
Describe how the innervation of limbs develops.
* Similar to muscle tissue, nerve axons migrate into the limb buds, with the brachial and lumbosacral plexuses forming.
* Motor axons attach to muscle territories and then lead sensory axons to their targets
136
Which spinal nerve roots grow into the upper and lower limbs?
* Upper limb = C5-T1/2
* Lower limb = L2-S2
137
Describe the development of limb ligaments, blood and tendons.
They are formed from the lateral plate mesoderm.
138
Describe limb rotation in development and when it happens.
* In the 6th to 8th weeks, the limbs rotate around their long axes.
* Upper limbs rotate laterally
* Lower limbs rotating medially (to a greater extent).
* The result of this is the distortion of the dermatomes, so that they appear twisted.
139
What is responsible for left-right assymetry of the body in development?
The primitive node:
* Cells of the node have prominent cilia, which rotate, creating flow
* Fluid flows from one side to the other generating asymmetry
* Nodal flow leads to asymmetric gene expression
140
What is situs inversus and what can cause it?
* A condition in which the major visceral organs are reversed or mirrored from their normal positions.
* It can be caused be defects in the cilia of the cells of the primitive node
141
What is the purpose of embryonic folding?
Converts the flat trilaminar germ disc into 3D ‘cylindrical’ structure.
142
What are the two directions of embryonic folding? What planes are these viewed in?
* Longitudinal (viewed in the sagittal plane)
* Lateral (viewed in the transverse plane)
143
Summarise the overall driving force for embryonic folding.
Vigorous growth of the embryonic disc and amnion, accompanied by very little growth in the yolk sac.
144
Describe how longitudinal folding occurs.
* Notochord cells have vacuoles, which give them strength and stops craniocaudal rounding. This is due to turgor pressure.
* Neural tube, notochord and somites stiffen the craniocaudal axis on the ventral side -\> So that the curving occurs on the more flexible dorsal side of the embryonic disc, leading to two regions of folding
145
In cranial (longitudinal) folding, what structures are moved where?
In the cranial to caudal direction at the cranial end (before folding):
* Septum transversum -\> Mesoderm that will fold into the thoracic region -\> Forms diaphragm and part of stomach and duodenum
* Cardiogenic region (will form the heart) -\> Moved to a position on the ventral side, inserting it into the thoracic region
* Oropharyngeal membrane (area where the ectoderm and endoderm are directly in contact without mesoderm in the middle) -\> Head folding moves this to the ventral side where the future mouth will be -\> Eventually forms the mouth
146
In caudal (longitudinal) folding, what structures are moved where?
In the caudal to cranial direction of the caudal end (before folding):
* Allantois -\> Part of endoderm that is contained within the connecting stalk -\> When the connecting stalk is moved by folding, it merges with the neck of the yolk sac -\> Allantois becomes part of the urinary system
* Cloacal membrane -\> Analogous to the oropharyngeal membrane in that it is a direct joining of the endoderm with the ectoderm, without a mesoderm layer in between -\> Becomes the future rectum
147
What is the driving force for lateral embryonic folding?
Embryonic disk grows, while the yolk sac does not grow -\> This results in a mushrooming effect.
148
Draw and describe the process of lateral folding.
* Embryonic disk grows, while the yolk sac does not grow -\> This results in a mushrooming effect
* Sides of amniotic sac move dorso-ventrally and latero-medially, so that they fuse at the ventral midline
* Lateral plate mesoderm has split into the somatic (upper, continuous with the amniotic mesoderm, will form the body wall) and splanchnic (lower, continuous with the yolk sac mesoderm, will form the surrounding of the organs) mesoderm -\> Upon folding, the endoderm and mesoderm layers become fused to the corresponding layers of the other side
* The space between the somatic and splanchnic mesoderm is initially open to the chorionic cavity, but upon fusion of the amniotic sac side, this cavity becomes enclosed within the embryo and is now called the intraembryonic coelom
* As folding occurs and the amniotic cavity sides fuse, the yolk sac is pinched to give the gut (which is surrounded by the intraembryonic coelom)
149
What important cavities are formed by lateral embryonic folding?
* Gut tube
* Intraembryonic coelom
* Amniotic cavity surrounds embryo
150
During embryonic folding, the neck of the yolk sac narrows. What is this structure now called?
Vitelline duct
151
Describe how the shape of the yolk sac changes during embryonic folding.
Starts off looking like a goldfish bowl but then the neck narrows.
152
What is the gut tube suspended in? What surrounds the gut tube and lines the cavity that it is suspended in?
* Gut tube is suspended in the coelomic cavity by the dorsal mesentry
* The gut tube is surrounded by splanchnic (visceral) mesoderm
* The body wall is lined internally by somatic (parietal) mesoderm
153
Describe some congenital defects of the ventral body wall.
154
What is the amnion continuous with?
The ectoderm.
155
What happens to the lateral plate mesoderm during embryonic folding?
It divides into splanchnic (visceral) mesoderm and somatic (parietal) mesoderm.
156
Describe how the umbilical cord is formed.
The umbilical cord is the red and yellow tube you can see in the third picture.
157
What are the two main body cavities and how are they formed?
* Pericardial cavity (thoracic)
* Peritoneal cavity (abdominal)
They are separated (almost completely) by the septum transversum during embryonic folding.
158
What connects the pericardial (thoracic) and peritoneal (abdominal) cavities during development?
Pericardial-peritoneal cavities -\> These are gaps on the sides of the septum transversum.
159
What is the septum transversum and when does it appear?
* Appears on day 22
* Bar of mesoderm lying rostral to the cardiogenic region (after embryonic folding moves it there)
160
What does the septum transversum give rise to?
Diaphragm
161
What are the attachments of the septum transversum?
* Anterior body wall (T7)
* Lateral body wall
* Oesophageal mesentery (T12)
162
During development, the two main body cavities are the pericardial (thoracic) and peritoneal (abdominal). Which of these is then partitioned further and how?
The pericardial cavity is partitioned into the pericardial and pleural cavities by outgrowth of the pleuropericardial folds from the body wall:
* Pleuropericardial folds grow and fuse medially subdividing the primitive pericardial cavity into a definitive pericardial cavity and two pleural cavities
* The root of the pleuropericardial folds then migrate around to the anterior body wall, forming the definitive pericardium
163
Describe the formation of the diaphragm.
* Septum transversum forms the amuscular central tendon
* Pericardioperitoneal canals closed by pleuroperitoneal membranes that contribute to the posterior musculature
* Dorsal oesophageal mesentery (L1-L3) give rise to the diaphragmatic crura
* Body wall musculature form the circumferential muscular rim (segmental thoracic innervation (T7-T12)
164
Describe the formation of the lungs. [COVERED LATER SO DW]
165
What structure does heart formation begin with? How does it form?
Horseshoe-shaped cardiogenic region (a.k.a. cardiac cresent):
* This forms when angiogenic clusters of blood vessels coalesce to form heart fields
* These eventually form a cresent shape
* The two sides are the left and right heart tubes
166
Describe how the left and right heart tubes form a single heart tube.
Lateral embryonic folding causes the two sides to fuse along the midline.
167
Which direction does blood flow through the early heart tube?
Caudal to cranial
168
Label this early heart tube. Which way does blood flow through it?
Blood flows caudal to cranial.
169
What do the different parts of the primitive heart tube go on to form?
* Truncus arteriosus -\> Aorta and pulmonary tract
* Bulbus cordis and primitive ventricle -\> Ventricles
* Primitive atrium -\> Atria
* Sinus venosus -\> SAN and coronary sinus
170
What are the different layers of the early heart tube? [IMPORTANT]
* Endothelium -\> This is the initial structure that forms the heart
* Cardiac jelly -\> This is the ECM secreted by the myocardium that lies between the endothelium and epicardium
* Myoepicardium -\> This is the mesoderm that surrounds the endothelium of the heart
171
What is the cardiac jelly made of?
* It is an ECM secreted by the myocardium (mesoderm).
* Contains: Hyaluronic acid + Proteoglycans
172
Where does blood leave the primitive heart and what does it flow into?
* Leaves via the bulbus cordis
* Enters the aortic arch, which passes over the developing gut and into the paired dorsal aorta
173
What is the early heart tube attached to and is this permanent?
* The linear heart tube is attached to the body by the dorsal mesocardium
* This breaks down, freeing the heart tube, allowing it to grow and change shape
174
When does looping of the heart tube take place?
Days 23-28
175
Describe heart looping.
The atria move behind the linear heart tube and come to lie superior to the primitive ventricle.
176
Label this heart after looping.
177
Give a one word phrase to describe heart looping.
Dextral (the heart bends to the right)
178
Describe how left-right asymmetry of the heart is created. [EXTRA]
179
When does septation of the heart take place?
Weeks 4-7
180
Describe the formation of the endocardial cushions. What does their formation allow?
The endocardial cushions form between the primitive atria and ventricles:
* Endocardial cushions begin as mesenchymal masses on the superior and inferior walls of the heart (noting that the heart is at an angle in the adult chest, so that the left wall is superior).
* Eventually, they form a barrier between the atria and ventricles, with only two atrioventricular canals remaining unclosed.
* The endocardial cushions enable septation to occur.
181
Describe the process of atrial septation.
* The septation of the atria occurs by the formation of the **septum primum**, which grows down from the atrial wall to fuse with the endocardial cushions.
* After this, holes form in the septum that converge to form the **ostium secundum**, a hole in the septum.
* To the right of the septum primum, the **septum secundum forms**, with a large hole called the **foramen ovale**.
* The ostium secundum and foramen ovale allow blood flow from the right atrium to the left atrium (bypassing the developing pulmonary system), but not vice versa.
* The foramen ovale is sealed closed later in development.
182
What are these:
* Septum primum
* Septum secundum
* Ostium primum
* Ostium secundum
* Foramen ovale
* Septum primum -\> The first mass to grow down from the top of the atria
* Septum secundum -\> The second mass to grow down from the top of the atria, more to the side of the right atrium
* Ostium primum -\> The gap between the septum primum and the endocardial cushions as the septum grows down
* Ostium secundum -\> The series of gaps that form in the septum primum after it has fused with the endocardial cushions
* Foramen ovale -\> The gap in the septum secundum left by the septum never fully fusing with the endocardial cushions
183
What does the foramen ovale allow?
* It allows shunting of blood from the right atrium to the left atrium, since it is oxygen-rich blood from the placenta.
* This means the non-functioning lungs are bypassed.
184
The foramen ovale acts to bypass the lungs in the developing embryo. However, some blood stills gets into the right ventricle and pulmonary circulation. What is done about this?
The ductus arteriosus shunts the blood to the aorta.
185
In the developing heart (before ventricular septation, etc.) describe the inflow and outflow of blood.
The blood flow through the heart is in two separate streams:
* Blood from placenta (high in O2 and nutrients) enters the Right Atrium via the IVC and tends to flow through foramen ovale into Left Atrium
* Blood returning from embryo (lower in O2 and nutrients) enters Right Atrium via SVC and flows into right side of the ventricle
* Both left and right ventricular blood leaves heart via Truncus Arteriosus
186
Describe ventricular septation.
The interventricular septum forms from the base of the heart, becoming less muscular and increasingly membranous towards the endocardial cushions it fuses with.
187
What is the part of the heart that is most susceptible to congential defects?
Ventricular septum
188
Describe the septation of the outflow tract of the heart.
* The septation of the ventricles carries on in the truncus arteriosus, with the septa turning throughout the outflow tract due to the blood flow over them.
* The spiral ridges in the outflow tract are called conotruncal ridges -\> These fuse together, dividing the outflow tract
As a result, the truncus arteriosus later divides into the aorta and pulmonary trunk, which end up twisted around each other.
189
What are some factors that are important in the septation of the ventricles and outflow tract of the heart?
* Haemodynamic forces
* Deformability of the heart wall
* Cell proliferation
190
What cells contribute to the formation of conotruncal ridges (in the outflow tract of the heart) and what is the significance of this?
* Neural crest cells which arise from occipital region populate the conotruncal ridges of the outflow tract
* Neural crest abnormalities are commonly linked with heart abnormalities
191
Describe the formation of the atrioventricular valves.
* Form between 5th-8th week
* Endocardial cells migrate into the cardiac jelly
* Ventricular layer is hollowed out and thinned by cell death to form valve leaflet
192
Give a congenital abnormality of the endocardial cushions.
* Failure of the endocardial cushions to fuse with the atrial or ventricular walls leads to persistent atrioventricular canal
* It is possible for deoxygenated blood and oxygenated blood to flow freely between all 4 chambers of the heart.
* This leads to difficulty breathing and cyanosis (blue discolouration of skin).
193
Give a congenital abnormality of the foramen ovale.
Failure of the closure leads to poor oxygenation of blood due to the partial bypassing of the lungs, leading to cyanosis, fatigue and shortness of breath.
194
Give a congenital abnormality of ventricular septation.
* Ventricular septal defect is the main cause of Tetralogy of Fallot.
* This is a rare series of events that results in pulmonary stenosis, mis-aligned aorta and right ventricular hypertrophy.
195
What are the 4 characteristics of the Tetralogy of Fallot?
1. Pulmonary Stenosis
2. Interventricular Septal Defect
3. Over-riding Aorta
4. Hypertrophy of Right Ventricle
196
What are the 3 main pairs of arteries draining the early embryo? What do they drain into?
* Vitelline veins
* Cardinal veins
* Umbilical veins
They all drain into the sinus venosus of the early heart.
197
What do the vitelline veins drain in the early embryo?
Yolk sac
198
What do the cardinal veins drain in the early embryo?
Body
199
What do the umbilical veins drain in the early embryo?
Placenta
200
Draw the circulatory system at 28 days.
201
Before septation of the atria, describe the bias of the venous supply.
There is a bias towards venous inflow into the right atrium over the left atrium.
202
What joins the truncus arteriosus to the dorsal aorta?
Aortic arches
203
How many aortic arches are there?
5 -\> They are numbers 1, 2, 3, 4 and 6 (since 5 is a residual)
204
Describe what happens to each of the aortic arches.
The aortic arches start to remodel to form the separate aortic and pulmonary trunks at end of 4th week:
* Arch I and II regress quickly
* Arch III forms the carotid arteries
* Arch IV and VI form aortic arch and pulmonary trunk
205
What is the ductus arteriosus?
A vessel between the pulmonary arch and the aortic arch, which acts as a by-pass for pulmonary circulation in the embryo.
206
Describe how the venous system changes in the embryo.
The system is initially bilaterally symmetrical but is remodelled so that all the systemic venous blood drains into the right side of the heart via the superior and inferior vena cava.
207
What are the main blood shunts open in the circulation before birth?
* Ductus venosus
* Foramen ovale
* Ductus arteriosus
208
Describe the changes that occur in the circulation at birth. [IMPORTANT]
* Upon 1st breath, the lungs expand and there is pulmonary return to left atrium so pressure increases
* RA pressure is less than LA pressure so the inter-atrial shunt via the foramen ovale closes -\> Forms the fossa ovalis
* Ductus arteriosus shuts due to bradykinins from lungs, changed O2 tension and the rise in maternal prostaglandin E2 -\> Becomes the ligamentum arteriosum
* Umbilical artery walls contract so blood flow to placenta from the baby stops -\> Becomes the medial vesicular ligament
* Umbilical vein closes slowly -\> Becomes ligamentum teres
* Ductus venosus closes -\> Becomes the ligamentum venosum
209
What does the foramen ovale form after birth?
Fossa ovalis
210
What does the umbilical artery become after birth?
Medial vesicular ligament
211
What does the umbilical vein become after birth?
Ligamentum teres
212
What does the ductus venosus become after birth?
Ligamentum venosum
213
