embryology Dr Alice Roberts PDF

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Notes by Dr Roberts on embryology, including the first 3 weeks and hoe the digestive system develops...

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Handbook of Embryology for Medical Students A guide to the three week course by Professor Alice Roberts Over three weeks, we’ll explore the wonderful world of human development, and find out how a single cell, a fertilised egg, develops into a small body with arms and legs, and internal organs including a beating heart. Studying embryology is useful for fetal medicine, of course, but it also helps to explain some of the peculiarities of adult anatomy, as well as how congenital defects come about. Embryology, like anatomy more generally, is a very visual subject, so I have made a series of videos for you, where I draw and paint the developing embryo. Drawing can help you to learn. Even if you don’t think you’re any good at drawing, I’d encourage you to have a go. You might be surprised - and find you’re actually better at it than you thought. Drawing’s a skill that improves with practice, and you may find it proves helpful for other learning. Some students find it useful to make 3D models out of plasticine, too. You might decide you even want to create your own embryology sketchbook as you watch the videos. You can stop and start them whenever you like, and even add extra notes from the content in this handbook, and the textbook too. The two textbooks I recommend for embryology are Langman’s Medical Embryology and Larsen’s Human Embryology. I’ve written this handbook as a guide for your learning - to help you plan your studies. But it isn’t intended to replace the textbooks. You are welcome to go at your own pace, of course, but I have divided the content over three weeks here. You’ll be learning a lot of new terminology and grappling with how the embryo and its organs change over time, so you may find it better to spread out your learning over the weeks as I’ve suggested. I’ll also host one or two drop-in sessions to iron out any problems and answer your questions. I’d love to see some of your artwork in those sessions too, so do bring your sketchbooks along.

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Week One In this first week of the course, we’ll explore the first four weeks of embryonic development, starting with the fertilised egg, and ending up with the formation of the basic body shape of the embryo. There are five videos to watch this week, and I’ve included supplementary notes to go with each video here, as well as suggesting which chapters of the textbook you should read to help consolidate your learning. Watch: Lockdown Embryology #1: The first week Lockdown Embryology #2: Week 2 Lockdown Embryology #3: Week 3 Lockdown Embryology #4: Week 4 Lockdown Embryology #5: Embryonic Folding

Lockdown Embryology #1: The first week This first video starts with fertilisation and ends with the tiny embryo, known as a blastocyst at this stage, implanting in the lining of the womb. Read: Langman’s Chapter 3 Principles of embryology • We divide human development in utero into the embryonic period (the first 8 weeks) and the fetal period (the remaining 32 weeks) • Systems develop before their function is required (luckily!) • The embryo is most susceptible to teratogens (factors that cause birth defects) between the third to eighth weeks of gestation (the period of embryogenesis/organogenesis) Processes in embryology • Growth - occurring by increase in cell numbers, increase in size of cells or increase in volume of extracellular matrix • Differentiation - of stem cells into specialist cell types • Cell migration - some cells move a long way from their origin • Cell death - hollowing out rods of tissue into tubes, for example Fertilization • Ovulation - an ovum is released from the ovarian follicle and swept up into the oviduct by cilia and muscle contractions of oviduct

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Fertilization normally occurs in the wide ampulla of the oviduct - sperm have travelled from the upper vagina, through the uterus, into the oviduct The sperm penetrates the cumulus oophorus, corona radiata and zona pellucida around the ovum, then the membranes of the sperm and ovum fuse Ovum completes meiosis The male and female pronuclei fuse, bringing 46 chromosomes together briefly, before the first round of cell division starts

Contraceptive methods Contraception is deigned to prevent fertilisation, either physically preventing contact between sperm and egg, physically blocking implantation, or hormonally reducing egg and sperm production. •

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Physical blocks include barrier methods (eg: condoms, diaphragm); intrauterine devices to block sperm or prevent embryo implantation; surgical methods (vasectomy in men; tubal ligation or blocking in women) Hormonal methods: female contraceptive pill (oestrogen and/or progestin inhibits ovulation); male pill (synthetic androgen reduces sperm production); emergency contraceptive pills: high dose progestin or hormone blocker initiates menstruation

Infertility • Around 15% couples experience fertility problems • Male infertility: too few sperm or poor motility; normal ejaculate is 2-6ml with 20-100 million sperm per ml - anything less may cause problems • Female infertility: blocked oviducts following pelvic inflammatory disease; hostile cervical mucus; immunity to sperm; absence of ovulation, etc. Assisted reproduction • IVF (in vitro fertilization) or ICSI (intracytoplasmic sperm injection) • In IVF: gonadotrophins given to stimulate ovary; oocytes are collected laparoscopically • sperm are added to egg; 8 cell stage embryo placed in uterus • IVF - 30% successful after first attempt in younger couples

4 Following fertilisation: Formation of the morula • Rapid cell division (cleavage) begins immediately: 1st division occurs within 24h; 2nd division occurs within 48h; 6-12 cells by 3 days: morula (‘mulberry’) • Day 4 - morula undergoes compaction – tight junctions form between cells • 2 sets of cells become distinct: inner cell mass (embryoblast) – will form embryo outer cell mass (trophoblast) – will form part of placenta Formation of the blastocyst • Day 4-5 - fluid enters the ball of cells – morula transformed into hollow blastocyst • Inner cell mass lies at the embryonic pole of the blastocyst Implantation • Day 6: blastocyst ‘hatches’ from the zona pellucida – and begins to implant in the endometrium (in its secretory phase - growing under influence of progesterone from the corpus luteum) • Trophoblast cells secrete human chorionic gonadotrophin (hCG) – maintains uterine lining • hCG levels high enough to be detected by end of 2nd week - basis of pregnancy tests • The implanted embryo employs mechanisms to suppress immune system and block recognition as foreign tissue – so it's not attacked by mother’s immune system Failure of implantation • 10% blastocysts though to fail to implant • Around 15% of detected pregnancies miscarry - but true figure for miscarriage is closer to 50% • Abnormalities in blastocyst include absent embryoblast - trophoblast may develop into hydatidiform mole (which may miscarry or be detected in routine US scan) • Many human embryos (>70%) contain major chromosomal abnormalities (from IVF studies) - embryonic signalling disrupted, causing uterine stress response - implantation less likely (Brosens et al. 2014) • This ‘natural screening’ reduces the rate of birth defects • Some embryos with chromosomal abnormalities do implant - antenatal tests are available for various genetic defects; advances in genetics and the scope of screening present ethical dilemmas for individuals and society as a whole

5 Ectopic pregnancy • Blastocyst implants in abnormal site, eg: peritoneal cavity, oviduct • Most ectopic embryos die in 2nd month – causing haemorrhage; ruptured oviduct may require emergency surgery.

Lockdown Embryology #2: Week 2 The embryo has implanted in the uterus. Now it starts to grow and differentiate, and we see the development of the two-layered germ disc that will develop into a tiny body, and the proliferation of tissues that will form the placenta. By the end of the second week, the embryo is attached to the early placenta by a connecting stalk - the precursor of the umbilical cord. Read: Langman’s Chapter 4

Week 2 – the ‘week of twos’ • Trophoblast differentiates into TWO layers: cytotrophoblast & syncytiotrophoblast • Embryoblast differentiates into TWO layers: epiblast & hypoblast (bilaminar germ disc) • The original blastocyst cavity is lined with hypoblast cells – becomes the yolk sac cavity – facing the hypoblast • Some yolk sac cells form a new layer: the extraembryonic mesoderm • TWO brand new cavities form: amniotic cavity within epiblast & chorionic cavity within extraembryonic mesoderm • The extraembryonic (chorionic) cavity expands until the embryo is suspended by a stalk of extraembryonic mesoderm: the connecting stalk (precursor of the umbilical cord) • Uteroplacental circulation starts - lacunae in syncytiotrophoblast open into large capillaries (sinusoids) in endometrium

6 Lockdown Embryology #3: Week 3 The week of GASTRULATION. Watch the transformation as a two-layered embryo becomes a three-layered embryo. You looked like a jam sandwich when you were this young. Read: Langman’s Chapter 5

Gastrulation • Primitive streak appears in week 3 • Establishes longitudinal axis and bilateral symmetry of embryo • Epiblast cells proliferate and migrate through the primitive streak: gastrulation • 3 germ layers formed: ectoderm, mesoderm, endoderm - forming the trilaminar germ disc • Mesoderm cells migrate through the primitive pit to form the notochord (replaced later by vertebral column) Buccopharyngeal and cloacal membranes • Depressions visible on ectoderm - where ectoderm tightly fused to endoderm • Later become the blind ends of the gut tube • Buccopharyngeal membrane will perforate in week 4 to form opening of mouth • Cloacal membrane will perforate in week 7 to become openings of anus and urogenital tracts Genes and fate maps • The differentiation of regions is governed by expression of genes, eg: cerberus in head region, Nodal in primitive streak • The fate of gastrulating epiblast cells can be mapped by cell tracing studies Gastrulation and teratogenesis • Gastrulation may be disrupted by genetic abnormalities and toxic insults • High doses of alcohol can kill cells in anterior midline of germ disc – affecting face and brain development • Situs inversus – transposed thoracic and abdominal viscera – often associated with organ defects • Caudal dysgenesis – insufficient caudal mesoderm leads to abnormal lower limbs (sirenomelia), kidneys, etc • Sacrococcygeal teratomas – from persistent remnants of primitive streak, most common tumours in newborn (1 in 37,000)

7 Fates of the germ layers Germ layers will give rise to adult tissues & organs: • Ectoderm forms epidermis & nervous tissue • Mesoderm forms skeletal, muscular & circulatory systems & connective tissues • Endoderm forms digestive & respiratory tracts

Lockdown Embryology #4: Week 4 This one’s about you make a neural tube out of a flat sheet of ectoderm, how you roll up a flat trilaminar germ disc into a cylinder, and something called noggin. Read: Langman’s Chapter 6

Ectoderm • The notochord secretes substances including noggin and chordin which inhibit the growth factor BMP-4, causing the overlying ectoderm cells form the neural plate or neurectoderm • In week 4, the flat neural plate rolls up into the neural tube • The neural tube will form the brain and spinal cord • Other ectoderm (in the presence of BMP-4) becomes epidermis • The otic and lens placodes are thickenings of ectoderm that will form the labyrinth of the ear and the lens of the eye • Ectoderm also gives rise to subcutaneous glands, pituitary gland and tooth enamel Mesoderm • Mesoderm condenses into 3 columns on each side • Paraxial mesoderm forms paired segments: somites - appear in a craniocaudal sequence; ‘segmentation clock’ depends on cyclic expression of several genes in mesoderm • Each somite divides into: sclerotome; myotome; dermatome; molecular signals from neural tube and notochord (sonic hedgehog and noggin) induce sclerotome to differentiate • Intermediate mesoderm forms urogenital structures • Lateral plate mesoderm pulls apart at the edges of the germ disc - to form a visceral/splanchnic layer lining yolk sac/organs and a parietal/somatic layer lining inside of body wall • Growth of somites causes lateral folding of the embryo and encloses intraembryonic cavity

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Endoderm • Development of the brain causes cephalocaudal folding of the embryo – encloses part of the endoderm-lined cavity inside the embryo as the primitive gut tube • Foregut finishes blindly at buccopharyngeal membrane • Midgut still attached to yolk sac (outside the body of the embryo) via yolk sac duct/vitelline duct • Hindgut finishes blindly at cloacal membrane

Lockdown Embryology with Prof Alice Roberts #5: Embryonic Folding How do you start to make a body - out of a flat disc? The answer lies in the folding that happens throughout weeks 3 and 4, when the trilaminar germ disc curls from head to toe and side to side and ends up looking like a cross between a sausage and a pea pod. Consequences of embryonic folding • Flat trilaminar germ disc converted into cylinder of nested endoderm, mesoderm and ectoderm tubes • Brings ectoderm to cover the outside of the body – encloses endoderm, mesoderm and intraembryonic cavity • Pulls the amniotic cavity around the developing embryo – and pushes the connecting stalk and vitelline duct together to form the umbilical cord

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Week Two In this second week, we’ll look at the development of the membranes that form the life-support system for the embryo and fetus in utero, and we’ll also start to explore the development of organ systems, starting with the digestive system. There are four more videos to watch this week, and once again, there are supplementary notes to go with each video here, and I’ve suggested which chapters of Langman’s you should read as well. I hope those sketchbooks are coming along nicely. Watch: Lockdown Embryology #6: Membranes Lockdown Embryology #7: Wrapping and Dividing Lockdown Embryology #8: Looping and Twisting Lockdown Embryology #9: Digestive organs

Lockdown Embryology #6: Membranes Membranes enclose the amniotic fluid that the embryo swims in - and form the placenta, the embryo’s life-support system in utero. Here I start by looking at the membranes inside a hen’s egg, supporting the developing chick embryo, then focus on equivalent membranes around the human embryo, and look at how the placenta develops over time to bring the fetal and maternal blood very close and facilitate exchange of gases, nutrients and waste. Read Langman’s Chapter 8.

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Fish and amphibians eggs contain yolks but lack extraembryonic membranes – their eggs must be laid in water Extraembryonic membranes (inner amnion, outer chorion) evolved in terrestrial vertebrates (reptiles, birds, mammals - aka amniotes) - as an adaptation to life on land, forming a fluid-filled capsule in which the embryo floats In egg-laying vertebrates (reptiles, birds and some primitive mammals): • the ovum has a large yolk (macrolecithal), full of yolk platelets, to supply the developing embryo with the nutrients it needs (albumen and shell added after fertilisation);

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Cell division occurs in a small area of the fertilised egg, to form an embryonic disc, sitting on the yolk; waste from the embryo is stored in an outpouching of the gut tube - the allantois; the membrane around the allantois fuses with the chorion and contains many blood vessels - this chorioallantoic membrane lies against the eggshell and facilitates gas exchange

In placental mammals (including humans), the egg develops inside the female body: • the ovum has no yolk (microlecithal) - as the mother will supply the developing embryo with nutrients • the entire fertilised egg or zygote divides to form the morula; • Waste is transferred to the mother’s body across the placenta • Gas exchange - from maternal to feral blood - occurs across the placenta

Functions of extraembryonic membranes • to store or remove waste products • to transport nutrients • to exchange gases (supply oxygen, remove carbon dioxide) • to create an aquatic environment for the developing embryo Membranes & placenta appear early in development and grow to meet the increasing demands of the growing embryo/fetus. The baby breaks free of its membranes at birth – then must depend on its own organs for nutrition, excretion and gas exchange. Extraembryonic membranes in placental mammals (including humans) • Amniotic cavity develops early, in epiblast • Yolk sac forms but contains no yolk platelets – only fluid • Allantois grows and fuses with chorion, forming the fetal part of the placenta (allantoic vessels in reptiles and birds are equivalent to umbilical vessels in placental mammals) • The placenta functions to transfer oxygen and nutrients to fetus, and remove carbon dioxide and metabolic waste • The placenta also produces hormones (hCG then progesterone) to maintain the uterine lining and oestriol to stimulate growth of uterus and breasts

11 Formation of the placenta The placenta is formed from the trophoblast and extraembryonic mesoderm (chorion) of the embryo - together with the adjacent endometrium of the uterus. In week 2 of development: • From day 9, small cavities called lacunae form in the syncytiotrophoblast and at the same time, maternal capillaries are enlarging to form sinusoids • Around day 12, the lacunae and sinusoids join up and the uteroplacental circulation is established; at the same time, extraembryonic mesoderm is forming, and cavitating to create the extraembryonic (or chorionic) cavity which expands until the embryo is suspended by its connecting stalk of extraembryonic mesoderm • The extraembryonic mesoderm lining the inside of the cytotrophoblast is also known as the chorionic plate From week 4: • Lacunae have expanded and and cytotrophoblast has grown to form fingerlike villi - and an outer cytotrophoblast shell • Stem or anchoring villi reach from chorionic plate out to the cytotrophoblast shell; free villi branch from the stem villi • Primary chorionic villi are protrusions of cytoptrophoblast • Secondary chorionic villi contain an extraembryonic mesoderm core • Tertiary stem villi contain capillaries within the mesoderm core • Lacunae grow larger - forming intervillous spaces, full of maternal blood supplied by spiral arteries From week 8: • The chorion around the attachment of the umbilical cord becomes more bushy - chorion frondosum; the chorion opposite the embryo becomes smooth - chorion laeve • The endometrium is now called the decidua (as it will be shed at birth): the decidua basalis is in contact with chorion frondosum; the decidua capsularis encloses the implanted embryo; the endometrium elsewhere is called the decidua parietalis • Cytotophoblast layer progressively lost from many villi - so the barrier between metal blood and maternal blood is just the endothelium of the villous capillary and a thin layer of syncytium; placenta brings fetal and maternal blood very close – but no mixing of blood • Villi produce large surface area for exchange of gases, nutrients, wastes between maternal and fetal blood • Some cytotophoblast cells incorporate themselves into the walls of the maternal spiral arteries - increasing their diameter and lowering their resistance.

12 Pre-eclampsia • This condition involves maternal hypertension and proteinuria (protein lost in urine) and affects about 5% of pregnant mothers • Pre-eclampsia tends to start after 20 weeks gestation and can be dangerous for both fetus and mother • The precise cause is unknown but seems to involve a lack of cytotophoblast cells fusing with maternal arteries; risk factors include pre-existing hypertension or diabetes, eclampsia in previous pregnancies and obesity What happens to all the cavities? • In weeks 4-8, the amniotic cavity grows larger and obliterates the chorionic (extraembryonic) cavity - the...