Embryology PDF - BMS 150 Week 8

Embryology Fertilization to Gastrulation BMS 150 Week 8 Introduction to Embryology Why learn embryology? Fascinating field of biology § We start out as one generalized, totipotential cell à 100 trillion cells, the vast majority of which ar...

Embryology Fertilization to Gastrulation BMS 150 Week 8 Introduction to Embryology Why learn embryology? Fascinating field of biology § We start out as one generalized, totipotential cell à 100 trillion cells, the vast majority of which are highly specialized § Within minutes after birth we undergo massive changes: Fetus - an organism that breathes no air, does not use the digestive tract and lives in a sterile environment Newborn - an air-breathing organism with a functional GI tract that quickly becomes colonized by microbial flora Introduction to Embryology Why learn embryology? Clinical relevance – a basic knowledge of embryology is essential to understanding: § Common categories of developmental/congenital disorders (just a few listed here): Immune system – DiGeorge syndrome Cardiovascular – abnormalities of the great vessels and valvular/septal structures of the heart Respiratory – neonatal respiratory distress syndrome Nervous system/otolaryngology – neural tube defects, developmental head and neck disorders Reproductive system – gestational trophoblastic disease, ectopic pregnancy § Infertility § Referred pain Introduction to Embryology Human development is complex, so it is important to categorize your knowledge What categories? § The age of the embryo/fetus – we want you to know what’s happening at each week, especially early in development § What structures have appeared… or disappeared Some people like to think about the rough size of the embryo § If you link information all together, then it will help you form a complete picture i.e. at week 3: Introduction to Embryology A simple table won’t be enough to build your understanding, though it will help. Other strategies include: 1. Identify a particular event § i.e. gastrulation 2. Define the event in 1-2 bullet points § What does it mean? What are the key features (beginning, ending, purpose)? 3. Describe the event as a series of steps that link to each other 4. Describe the relevance of the “end product” § This could be very short or long, depending on the event Introduction to female reproductive anatomy Reproductive anatomy will be covered in much more depth in Biomedicine in Year 2 Essentials will be discussed here as they relate to fertilization and implantation of the embryo Introduction to female reproductive anatomy Ovaries: § Production of oocytes Female haploid gametes § Production of progesterone and estrogens Uterine tube (Fallopian tube): § Receives oocyte from ovaries § Site where sperm fertilizes the oocyte Uterus § Site where the embryo develops § Site where the placenta and membranes develop Placenta = site where the maternal and embryonic vasculature exchange substances Basics of ovulation and fertilization Remember meiosis? § A diploid cell (germ cell) undergoes meiosis to produce a unique haploid gamete Unique à crossing-over between maternal and paternal chromatids during prophase I to end up with “mixed” chromatids “mixed” = some paternal, some maternal genes Meiosis is not completed in an oocyte until the sperm penetrates the oocyte § Spermatic pronucleus and the oocyte pronucleus fuse, thus completing fertilization Combination of spermatic and oocyte genetic material à diploid cell § Single diploid cell = zygote  Basics of ovulation and fertilization A person with ovaries is born with a certain number of diploid oocytes that have been “paused” during the first stage of meiosis – do not continue meiosis until after puberty After puberty, the ovaries release an ovum each cycle into the uterine tubes § The oocyte will not complete meiosis II unless fertilization occurs § Fertilization typically occurs in the ampulla of the uterine tube  Ovulation - release of a secondary oocyte from ovarian follicle Ovulated secondary oocyte together with zona pellucida, is externally covered with granulosa cells – cumulus oophorus Cumulus oophorus will rearrange and form corona radiata Basics of ovulation and fertilization Fertilization typically occurs in the ampulla of the uterine tube Sperm cell penetrates the zona pellucida and “injects” its genetic material into the oocyte § Afterwards, the zona pellucida becomes impenetrable to other sperm cells (can’t have “double fertilization”) § After approximately 24 hours, the oocyte completes meiosis II and the zygote completes the first cell division This is the end of day 1, week 1  Key Events – Week 1 Ampulla of uterine tube Note the locations and the level of development of the embryo in each area of the female reproductive tract  Overview of fertilization Corona radiata = cells that surround the oocyte, found outside of the zona pellucida Sperm cells undergo several changes (discussed later) in the uterus to prepare them to inject the pronucleus across the zona pellucida into the oocyte Embryologic terms – fertilization to week 1 Gamete – a haploid germ cell § Oocyte – gamete from ovaries § Sperm – gamete from testes Fertilization – fusion of the pronucleus of the two gametes Zona pellucida – protein coat that surrounds an oocyte as well as the early embryo Zygote – a fertilized, diploid oocyte – has not yet divided Embryo – multicellular organism, prior to fetal stage § Arbitrarily defined as period from fertilization – end of week 7 Fetus – multicellular organism, from end of embryonic stage to birth Neonate – newborn Extraembryonic = cells formed during development that do not become part of the neonatal organism, but involute or contribute to the fetal membranes Embryologic terms – fertilization to week 1 Morula – approximately 16-cell stage (12 – 32 cells) of an embryo § No blastocoel Blastocyst – a spherical mass of cells that is composed of a trophoblast that surrounds a fluid cavity (blastocoel) and an inner cell mass (embryoblast) Cleavage – cell division in the early embryo à each division does not increase the size of the embryo, instead each division results in smaller and smaller cells Blastomere – a cell that is totipotential and is present during very early development (first week) § Product of cleavage § Totipotential = a cell that can become any cell Implantation – occurs when an embryo contacts and then becomes surrounded by the endometrium of the uterus  Early Embryology Overview: Week Key developmental steps Appearance 1 Begins with fertilization From a single From zygote to blastocyst cell to a “ball” of Inner cell mass (embryoblast), trophoblast, blastocoel cells “Hatching” from zona pellucida, first appearance of Size – 0.1 mm syncytiotrophoblast & cytotrophoblast Adhesion to endometrium (uterus) and beginning of implantation 2 Trophoblast develops into syncytiotrophoblast and cytotrophoblast Disk-shaped Embryo “sinks” beneath the endometrium embryonic cells Trophoblastic extensions begin to interface with maternal blood surrounded by extra-embryonic vessels cavities Embryoblast develops into a bilaminar disk – epiblast + hypoblast Size – 0.2 mm Prechordal plate develops at the end of this week Umbilical vesicle, extraembryonic coelom develop 3 Gastrulation: bilaminar disk à trilaminar disk Developing villi Three germ layers surround Notochord forms, and then the following develop à elongated, disk- shaped embryo Neural groove, neural plate, early neural tube with a few Paraxial mesoderm + somites somites Tertiary chorionic villi, heart tube, primordial circulation develop Size – 0.7 mm Early Embryology Overview Week 1 Week 2 Week 3 From zygote à blastocyst From days 1 – 3, the embryo develops from zygote to a sphere-shaped cluster of cells surrounded by the zona pellucida § 12 – 32 cell stage = morula (because it looks like a mulberry) § Cell divisions known as cleavage, cells known as blastomeres (all genetically identical – embryonic stem cells !) A fluid-filled cavity develops within the embryo, and four separate structures can be noted at this stage (days 4 - 5): § Trophoblast – layer of cells on the outside of the sphere Trophoblast is still covered by the zona pellucida Many of these cells develop into the membranes of placenta § Embryoblast (inner cell mass) – surrounded by the trophoblast, these cells develop into the embryo § Blastocoel – the fluid filled cavity within the sphere  From zygote à blastocyst Fertilization of the oocyte usually occurs in the ampulla of the uterine tube (see next slide) The epithelial cells of the uterine tube are equipped with cilia that “wave” in a single direction § Ciliary movement increases as progesterone levels increase (more later) Progesterone secretion peaks shortly after ovulation § After about 5 days, the blastocyst has arrived at the superior aspect (fundus) of the uterus Propelled by ciliary movement  Key Events – Week 1 Ampulla of uterine tube Note the locations and the level of development of the embryo in each area of the female reproductive tract From zygote à blastocyst Zona pellucida (ZP) plays many important roles early in development: § Barrier that ensures that only one sperm fertilizes an oocyte § Porous – allows communication between the embryo and the maternal reproductive structures § Protects the embryo from immunologic defenses § Acts as a signal to help with differentiation of trophoblast cells § Prevents premature implantation of the embryo § Prevents the blastomeres from dissociating Zona “hatching” and implantation The ZP prevents the early implantation of the embryo § If the embryo implants too early, it could result in an ectopic pregnancy (discussed later) At day 6, the embryo will “hatch” out of the ZP § The trophoblastic cells just over the embryoblast seem to secrete/produce particular proteinases that weaken the wall of the ZP § The blastocyst “hatches” through this defect in the ZP and is ready to contact the endometrium and implant itself within it The blastocyst and the endometrium need to “cooperate” for implantation to occur Zona “hatching” and implantation The endometrial epithelium expresses different types of mucin proteins as well as small apical processes known as pinopods § The trophoblast of the blastocyst (free of the ZP) contacts the pinopods and adheres to the endometrial epithelium § Adhesion is mediated by selectin (binds to mucins) and integrin binding, and results in the blastocyst invading into the endometrium Similar to leukocyte emigration from the bloodstream Once the trophoblast contacts the endometrial epithelium and invades, it forms two layers: § Cytotrophoblast – inner layer § Syncytiotrophoblast – outer layer that covers cytotrophoblast Occurs at days 5 - 6 Implantation of the blastocyst Note the pinopods on the uterine epithelium Syncytiotrophoblast Cytotrophoblast Implantation of the blastocyst Syncytiotrophoblast develops into a multinuclear cell “mass” where the borders between individual cells are indistinct The syncytiotrophoblast invades quickly and deeply into the endometrial stroma (area under the epithelial cell) and performs a number of important functions: § Invasion into the endometrial stroma and induction/formation of villi (later becomes the placenta) Proteinases and adhesion molecules perform this role § Secretion of human chorionic gonadotropin (hCG) hCG prevents the shedding of the endometrium (and loss of the embryo) by maintaining ovarian secretion of steroid hormones (i.e. progesterone) hCG is the hormone detected in pregnancy tests  End of Week 1 – days 6-7 As the syncytiotrophoblast invades into the stroma, the inner cell mass (embryoblast) differentiates into two distinct layers: § Epiblast This layer will become embryo proper § Hypoblast It will line the blastocystic cavity (coelom) and form the primary yolk sac Also known as the primary endoderm Overview of Week 2 13 14 9 12 10 Embryologic terms – Week 2 & 3 Coelom – a fluid-filled cavity Gastrulation – the process of forming three embryonic germ layers: § Ectoderm – a layer that is typically found on the “exterior” of the organism § Endoderm – a layer that is typically found on the “interior” of the organism § Mesoderm (intraembryonic mesoderm) – a layer found between the ectoderm and endoderm § Note – endoderm and mesoderm can also be extra- embryonic (formation of extra-embryonic endoderm and mesoderm is not classified as gastrulation) Cephalad – towards the head region (anatomical term) Caudad – towards the “tail” region (anatomical term)  Completion of Implantation Implantation of the embryo is complete at about day 10 § The embryo is completely embedded within the endometrium § Surrounded by syncytiotrophoblast cells The stromal cells (below the epithelium) undergo decidualization § Now known as decidual cells § Decidual cells accumulate glycogen and lipids throughout the uterus § The decidual cells that the syncytiotrophoblast contact undergo apoptosis, releasing stored nutrients needed for embryonic growth (until the placenta is better established) Epiblast and Hypoblast The epiblast enlarges and gives rise to amnioblasts § Amnioblast = cells that surround the developing amniotic cavity The hypoblast extends around the entire interior surface of the blastocoel § New class of cells begin to form and migrate between the hypoblast-derived cells (yolk sac or extraembryonic endoderm) and the cytotrophoblast. These cells form extraembryonic mesoderm § At this point, what was formerly the blastocoel is known as the primary umbilical vesicle / primary yolk sac The hypoblast and epiblast form the bilaminar disk  Epiblast and Hypoblast – Week 2 Note the migration of hypoblast cells à line the inner surface of the cavity Note the migration of hypoblast cells à Amnioblasts line the inner surface of the cavity Extra-embryonic mesoderm develops between the cytotrophoblast and the cells derived from the hypoblast (umbilical vesicle = yolk sac) Development of Extraembryonic Structures Fluid begins to accumulate between the extra- embryonic mesodermal cells to form another cavity that is known as the extraembryonic coelom At this point there are three distinct fluid-filled cavities developing in the embryo: § Umbilical vesicle (yolk sac) – as the embryo develops the primary umbilical vesicle becomes the smaller secondary umbilical vesicle § The amniotic cavity – found above the epiblast § Extraembryonic coelom – as this enlarges and develops, it will develop into the chorionic cavity Development of Extraembryonic Structures Note the accumulation of fluid spaces within the extra-embryonic mesoderm § At day 13 (bottom picture) that fluid space becomes the extra- embryonic coelom § Extraembryonic coelom completely surrounds the rest of the embryo everywhere except for at the junction of the amniotic cavity and the rest of the chorionic sac This junction will become the connecting stalk à this develops later into the umbilical cord Development of Extraembryonic Structures There are now two layers of extraembryonic mesoderm, separated by the fluid in the extraembryonic coelom: § Extraembryonic splanchnic mesoderm – surrounds the umbilical vesicle(s) § Extraembryonic somatic mesoderm – found just underneath the cytotrophoblast, inner lining of the chorionic sac Top picture – day 13 Bottom picture – day 14 (end of second week) Development of Extraembryonic Structures Chorion = extraembryonic somatic mesoderm + trophoblast = wall of chorionic sac Chorionic sac encloses the embryo and its cavities, and is surrounded by the syncytiotrophoblast § By day 14, the extraembryonic coelom is called the chorionic cavity The amniotic cavity, secondary umbilical vesicle, and bilaminar disk are “attached” to the chorion via the connecting stalk Top picture – day 13 Bottom picture – day 14 (end of second week) Development of Extraembryonic Structures Where syncytiotrophoblast contacts endometrial blood vessels, the blood vessel deteriorates and blood pools § Form “little lakes”, or lacunar networks The oxygenated maternal blood + glycogen/lipids from deteriorating decidual cells nourish the embryo § Simple diffusion from lacuna & decidual cells, no circulation yet § During day 13-14, the cytotrophoblast sends extensions to the lacuna to form primary villi Precursors of functional placental villi End of week 2 – Prechordal Plate At the end of week 2, the prechordal plate appears § Thickened area of columnar cells that acts as an organization area, found in the cephalad region of the hypoblast § An embryonic organizing centre that is responsible for the induction of other structures Induction = signaling “episodes” by key areas of the embryo that stimulate differentiation and development of local structures § The hypoblast is an organizer of the head and mouth region, and helps to induce the formation of structures found at the cephalad pole of the embryo § It also prevents the formation of structures that belong at the caudal aspect of the embryo End of week 2 – Prechordal Plate The prechordal plate and the nearby anterior visceral endoderm are important organizing centers § More to be discussed later Summary of implantation Implantation of the blastocyst in the uterine endometrium begins at the end of the first week and is completed by the end of the second week. Implantation may be summarized as follows: The zona pellucida degenerates (day 5). Its disappearance results from enlargement of the blastocyst and degeneration caused by enzymatic lysis. The lytic enzymes are released from the acrosomes of the sperms that surround and partially penetrate the zona pellucida. The blastocyst adheres to the endometrial epithelium (day 6). The trophoblast differentiates into two layers: the syncytiotrophoblast and cytotrophoblast (day 7). The syncytiotrophoblast erodes endometrial tissues and the blastocyst begins to embed in the endometrium (day 8). Blood-filled lacunae appear in the syncytiotrophoblast (day 9). The blastocyst sinks beneath the endometrial epithelium and the defect is filled by a closing plug (day 10). Lacunar networks form by fusion of adjacent lacunae (days 10 and 11). The syncytiotrophoblast erodes endometrial blood vessels, allowing maternal blood to seep in and out of lacunar networks, thereby establishing a utero-placental circulation (days 11 and 12). The defect in the endometrial epithelium is repaired (days 12 and 13). Primary chorionic villi develop (days 13 and 14). Summary of week 2 Rapid proliferation and differentiation of the trophoblast occurs as the blastocyst completes implantation in the uterine endometrium. The endometrial changes resulting from the adaptation of these tissues in preparation for implantation are known as the decidual reaction. Concurrently, the primary umbilical vesicle (yolk sac) forms and extraembryonic mesoderm develops. The extraembryonic coelom (cavity) forms from spaces that develop in the extraembryonic mesoderm. The coelom later becomes the chorionic cavity. The primary umbilical vesicle becomes smaller and gradually disappears as the secondary umbilical vesicle develops. The amniotic cavity appears as a space between the cytotrophoblast and embryoblast. The embryoblast differentiates into a bilaminar embryonic disc consisting of epiblast, related to the amniotic cavity, and hypoblast, adjacent to the blastocystic cavity. The prechordal plate develops as a localized thickening of the hypoblast, which indicates the future cranial region of the embryo and the future site of the mouth; the prechordal plate is also an important organizer of the head region. Week 3 - Gastrulation Gastrulation: The process by which the three germ layers of the embryo are established Ectoderm Mesoderm Endoderm Bilaminar embryonic disc becomes trilaminar embryonic disc Embryo may be referred to as a gastrula Week 3 – Process of Gastrulation At the beginning of the 3rd week, formation of the primitive streak appears Primitive streak = thickened linear band in the median plane of the dorsal aspect of the embryonic disc Initiates in the caudal region of the epiblast It results from proliferation and movement of epiblast cells to the median plane of the embryonic disc  Week 3 – Process of Gastrulation Cells at the cephalad end of the primative streak proliferate to form a primitive node Concurrently, a narrow groove — primitive groove — develops in the primitive streak This groove is continuous with a small depression in the primitive node known as the primitive pit  Week 3 – Embryonic Mesoderm Cells leave the deep surface of the streak and form mesenchyme § Mesenchyme = embryonic connective tissue which forms the supporting tissues of the embryo (i.e. embryonic connective tissue) Some mesenchyme forms mesoblastic cells (undifferentiated mesoderm) § The mesoblasts form the intraembryonic, or embryonic, mesoderm  Week 3 – Embryonic Mesoderm Cells from the epiblast, as well as from the primitive node and other parts of the primitive streak, displace the hypoblast § form the embryonic endoderm in the roof of the umbilical vesicle The cells remaining in the epiblast form the embryonic ectoderm Mesenchymal cells derived from the primitive streak migrate widely § These pluripotential cells differentiate into diverse types of cells – examples: Fibroblasts, chondroblasts, osteoblasts  Week 3 – Primitive Streak Later, the primitive streak diminishes in size and becomes an insignificant structure in the sacrococcygeal region Disappears by the end of the 4th week  Early Embryology Overview: Week Key developmental steps Appearance 1 Begins with fertilization From a single From zygote to blastocyst cell to a “ball” of Inner cell mass (embryoblast), trophoblast, blastocoel cells “Hatching” from zona pellucida, first appearance of Size – 0.1 mm syncytiotrophoblast & cytotrophoblast Adhesion to endometrium (uterus) and beginning of implantation 2 Trophoblast develops into syncytiotrophoblast and cytotrophoblast Disk-shaped Embryo “sinks” beneath the endometrium embryonic cells Trophoblastic extensions begin to interface with maternal blood surrounded by extra-embryonic vessels cavities Embryoblast develops into a bilaminar disk – epiblast + hypoblast Size – 0.2 mm Prechordal plate develops at the end of this week Umbilical vesicle, extraembryonic coelom develop 3 Gastrulation: bilaminar disk à trilaminar disk Developing villi Three germ layers surround Notochord forms, and then the following develop à elongated, disk- shaped embryo Neural groove, neural plate, early neural tube with a few Paraxial mesoderm + somites somites Tertiary chorionic villi, heart tube, primordial circulation develop Size – 0.7 mm Cell and tissue lineages  Week 3 – Intro to the Notochord Roles of the notochord: 1. Establishes the longitudinal axis of the embryo and gives it some rigidity 2. Provides signals for the development of axial MSK structures and the CNS 3. Contributes to the intervertebral discs  Week 3 – Intro to the Notochord Development of the notochord: mesenchymal cells dive into the primitive pit and migrate cephalad § they form a cord called the notochordal process § The notochordal process develops a lumen known as the notochordal canal § Pictures correspond to days 16, 17, and 18  Embryology Neurulation, Folding, and Development of the Nervous System Reference – Chapters 4 & 5 BMS 150 The Developing Human, 8th ed. Week 8 Moore, Persaud, & Torchia Cell and tissue lineages  Week 3 – The Notochord Roles of the notochord: 1. Establishes the longitudinal axis of the embryo and gives it some rigidity 2. Provides signals for the development of axial MSK structures and the CNS 3. Contributes to the intervertebral discs  Week 3 – The Notochord Development of the notochord: mesenchymal cells dive into the primitive pit and migrate cephalad ▪ they form a cord called the notochordal process ▪ The notochordal process develops a lumen known as the notochordal canal ▪ Pictures correspond to days 16, 17, and 18 Week 3 – The Notochord After the notochordal process approaches the prechordal plate, the floor of the process “fuses” with the endoderm ▪ The notochordal process is now the notochordal plate ▪ The amniotic cavity and the umbilical vesicle can communicate through an opening (the neurenteric canal) – this opening is where the primitive pit opened into the notochordal canal At this point, the notochordal plate cells proliferate and fold inwards, forming the fully-developed notochord ▪ No canal is present ▪ Notochordal plate ! notochord transition starts cranially and progresses caudally After the notochord is fully-developed, the neurenteric canal is obliterated Transformation of the notochordal process ! notochordal plate Middle of 3rd week Note the neurenteric canal, lack of endoderm in the floor of the plate Transformation of the notochordal plate ! notochord Middle of 3rd week Neural groove and different mesodermal regions visible, the notochord has no canal, and endoderm is present between the notochord and the umbilical vesicle The prechordal plate and notochord as organizers The notochord and its preceding structures (process, plate) are important organizers ▪ induce the overlying ectoderm to develop into the neural plate ▪ The notochord also serves as the central axis of the embryo – the divider between right and left ▪ The signaling mechanisms responsible for this induction are complex and will not be explored here The notochord structures approach the prechordal plate, but do not go beyond it ▪ As mentioned previously, the prechordal plate is an important organizer for development of cranial structures ▪ Also the “stop signal” preventing the notochord from developing too far anteriorly  Oropharyngeal and Cloacal Membranes The prechordal plate develops into the oropharyngeal membrane ▪ Two-layer membrane – ectoderm and endoderm, no mesoderm ▪ Cardiogenic mesoderm found anteriorly The cloacal membrane forms caudal to the primitive streak ▪ Also two layers – ectoderm and endoderm, no mesoderm ▪ Future site of the anus Allantois Small, vascularized diverticulum (outpouching) from the caudal wall of umbilical vesicle, extending into connecting stalk Functions in early blood formation and bladder development ▪ Blood vessels become umbilical arteries ▪ Small portion persists as urachus that extends from bladder to umbilical region Becomes median umbilical ligament in adults Day 18 Neurulation Notochord induces overlying ectoderm to form the neural plate ▪ Known as neuroectoderm ▪ Gives rise to the CNS, retina, and the tissues that arise from the neural crest ▪ Neuroectodermal cells are very tall and columnar in shape ▪ As the organism matures, the neural plate extends beyond the notochord On day 18, the neural plate invaginates to form the neural groove – neural folds are found on either side of the groove The neural folds eventually fuse together, and form the neural tube ▪ The neural tube is the primordium of the CNS Neurulation Neurulation is therefore the process by which the neural tube is formed Begins with neural plate formation Ends when the tube becomes completely “closed” – no opening at either the caudal or cephalic ends Weeks ▪ Neurulation is 3-4 complete at the end of the 4th week ▪ Note the location of the neural crest cells Neural Crest Cells Subset of neuroectodermal cells Originate from the “crest” at the apex of the neural folds Lose affinity to epithelium and Weeks neighbouring cells 3-4 Migrate dorso-laterally on either side of the tube Many migrate widely throughout the mesenchyme  Neural Crest Cells Derivatives of the neural crest include: ▪ Ganglia of CN V, VII, IX, X ▪ Spinal ganglia (i.e. dorsal root ganglia) ▪ Autonomic nervous system ganglia ▪ Neurolemma sheaths of peripheral nerves ▪ Contribute to the arachnoid and pia ▪ Adrenal medulla ▪ Melanocytes ▪ Craniofacial bone and cartilage ▪ Portions of the heart Intraembryonic Mesoderm During the 3rd week: ▪ Intraembryonic mesoderm proliferates to form a thick column of mesoderm on either side of the notochord Beside the axis of the organism (as defined by the notochord) = paraxial mesoderm ▪ The intermediate mesoderm is found just lateral to the paraxial mesoderm ▪ The lateral mesoderm is lateral to the intermediate mesoderm Somites During the 3rd – 5th week, somites develop adjacent to the neural tube Somite = cuboidal masses of mesoderm on either side of the notochord, visible along the dorso-lateral surface of the embryo on each side of the neural tube Formed from the paraxial mesoderm Somites give rise to most of the axial skeleton and associated musculature, as well as the dermis in those areas Intraembryonic Mesoderm During the 3rd week mesenchymal cells migrate anteriorly, lateral to the notochordal process to eventually form cardiogenic mesoderm ▪ Found anterior to the prechordal plate, eventually gives rise to the embryonic heart primordia ▪ The heart begins as a pair of tubes that are brought together by folding of the embryo (see later) Top – day 16, early in development of notochordal process Bottom – day 20 – heart primordium cephalad to the prechordal plate Intraembryonic Coelom The primordium of the intraembryonic coelom (embryonic body cavity) appears as isolated spaces in the lateral mesoderm and cardiogenic mesoderm ▪ These spaces soon coalesce (join together) and form a single horseshoe-shaped intraembryonic coelom Intra-embryonic coelom divides the lateral mesoderm into two layers: ▪ A somatic or parietal layer of lateral mesoderm located beneath the ectodermal epithelium and continuous with the extraembryonic mesoderm covering the amnion ▪ of lateral mesoderm next to the endoderm and continuA splanchnic or visceral layer ous with the extraembryonic mesoderm covering the umbilical vesicle Intraembryonic Coelom Note the horseshoe- shape of the intraembryonic coelom By about day 21 the coelomic spaces have formed a continuous cavity Intraembryonic Coelom Three general structures can be Day 19 seen in the region of the lateral mesoderm: ▪ Somatopleure – the somatic mesoderm and the overlying ectoderm Day Forms the body wall 20 ▪ Splanchnopleure – the splanchnic mesoderm and the underlying intraembryonic endoderm Forms the embryonic gut ▪ Intraembryonic coelom in Day between the somatopleure and 21 splanchnopleure Intraembryoni c Coelom During the 2nd month, the intraembryonic coelom develops into 3 main body cavities: ▪ Pericardial cavity ▪ Pleural cavity ▪ Peritoneal cavity Week 3 - Summary The bilaminar embryonic disc is converted into a trilaminar embryonic disc during gastrulation. These changes begin with the appearance of the primitive streak, which appears at the beginning of the third week as a thickening of the epiblast at the caudal end of the embryonic disc. The primitive streak results from migration of epiblastic cells to the median plane of the disc. Invagination of epiblastic cells from the primitive streak gives rise to mesenchymal cells that migrate ventrally, laterally, and cranially between the epiblast and hypoblast. As soon as the primitive streak begins to produce mesenchymal cells, the epiblast is known as embryonic ectoderm. Some cells of the epiblast displace the hypoblast and form embryonic endoderm. Mesenchymal cells produced by the primitive streak soon organize into a third germ layer, the intraembryonic or embryonic mesoderm, occupying the area between the former hypoblast and cells in the epiblast. Cells of the mesoderm migrate to the edges of the embryonic disc, where they join the extraembryonic mesoderm covering the amnion and umbilical vesicle. Early in the third week, mesenchymal cells from the primitive streak form the notochordal process between the embryonic ectoderm and endoderm. The notochordal process extends from the primitive node to the prechordal plate. Openings develop in the floor of the notochordal canal and soon coalesce, leaving a notochordal plate. This plate infolds to form the notochord, the primordial axis of the embryo around which the axial skeleton forms (e.g., vertebral column). Week 3 - Summary At the end of the third week, the embryo is a flat ovoid embryonic disc. Mesoderm exists between the ectoderm and endoderm of the disc everywhere except at the oropharyngeal membrane, in the median plane occupied by the notochord, and at the cloacal membrane. The neural plate appears as a thickening of the embryonic ectoderm, induced by the developing notochord. A longitudinal neural groove develops in the neural plate, which is flanked by neural folds. Fusion of the folds forms the neural tube, the primordium of the CNS. As the neural folds fuse to form the neural tube, neuroectodermal cells form a neural crest between the surface ectoderm and neural tube. The mesoderm on each side of the notochord condenses to form longitudinal columns of paraxial mesoderm, which, by the end of the third week, give rise to somites. The coelom (cavity) within the embryo arises as isolated spaces in the lateral mesoderm and cardiogenic mesoderm. The coelomic vesicles subsequently coalesce to form a single, horseshoe-shaped cavity that eventually gives rise to the body cavities. Blood vessels first appear in the wall of the umbilical vesicle (yolk sac), allantois, and chorion. They develop within the embryo shortly thereafter. Fetal and adult erythrocytes develop from different hematopoietic precursors – more to be discussed later The primordial heart is represented by paired endocardial heart tubes. By the end of the third week, the heart tubes have fused to form a tubular heart that is joined to vessels in the embryo, umbilical vesicle, chorion, and connecting stalk to form a primordial cardiovascular system – more to be discussed later  Embryonic Folding Embryonic folding is the process by which a relatively “flat” embryonic disk becomes more and more cylindrical in shape Folding occurs in two general planes ▪ The median plane – the anterior and posterior ends of the embryo move ventrally. Also known as cranial-caudal folding ▪ The horizontal plane – the lateral edges of the embryonic disk move ventrally. Also known as lateral folding The edges “roll” ventrally towards the umbilical vesicle Embryonic Folding Folding begins at the end of the 3rd week and is easy to see in the 4th week ▪ As it folds cranially, the brain vesicles first begin to appear, and a few somites are obvious ▪ As it folds laterally, the body wall is formed  Day 21 Day 22 Day 25 Day 28 Cranial Folding – Key Aspects Part of the endoderm of the umbilical vesicle is incorporated into the embryo as the foregut ▪ The foregut lies between the brain and heart ▪ Oropharyngeal membrane separates the foregut from the stomodeum ▪ Stomodeum = the primordium of the mouth Cranial Folding – Key Aspects Septum transversum lies caudal to the heart ▪ develops into the central tendon of the diaphragm and separates the abdominal cavity from the thoracic cavity Cranial Folding – Key Aspects The position of the heart changes due to the head fold: ▪ Heart moves to the ventral surface of the embryo ▪ pericardial coelom lies ventral to the heart and cranial to the septum transversum  Tail Folding – Key Aspects As the embryo grows, the caudal eminence (tail region) projects over the cloacal membrane (future site of anus) Part of the endodermal germ layer is incorporated into the embryo as the hindgut The connecting stalk (primordium of umbilical cord) is now attached to the ventral surface of the embryo, and the allantois is partially incorporated into the embryo  Lateral Folding – Key Aspects Lateral folding is caused by the rapidly growing spinal cord and somites As the abdominal walls form, part of the endoderm germ layer is incorporated into the embryo as the midgut Initially, there is a wide connection between the midgut and umbilical vesicle after lateral folding, the connection is reduced to an omphaloenteric duct ▪ The region of attachment of the amnion to the ventral surface of the embryo is also reduced to a relatively narrow umbilical region Germ Layer Derivatives - Overview  Germ Layer Derivatives The three germ layers (ectoderm, mesoderm, and endoderm) formed during gastrulation give rise to the primordia of all the tissues and organs Ectoderm: Mesoderm: Endoderm: CNS, PNS; sensory connective tissue; epithelial lining of the epithelia of the eyes, cartilage; bone digestive and respiratory ears, and nose striated and smooth tracts, parenchyma of the epidermis and its muscles; heart, blood, and tonsils appendages (hair and lymphatic vessels; kidneys; thyroid and parathyroid nails); mammary glands; ovaries; testes; genital glands, thymus subcutaneous glands; ducts; serous membranes liver, and pancreas, enamel of teeth; lining the body cavities epithelial lining of the pituitary gland (pericardial, pleural, and urinary bladder and most Neural crest cells – peritoneal); spleen; and of the urethra discussed previously cortex of suprarenal epithelial lining of the glands tympanic cavity, tympanic antrum, and eustachian tube  Development of the Nervous System - Overview The events of neurulation have already been discussed ▪ Neural plate can be seen at day 19 ▪ Neural plate ! neural groove ! neural tube ▪ Conclusion of neurulation with the closure of the neuropores (day 27) – at this point the neural tube no longer communicates with the amniotic cavity After neuropore closure, a basic blood circulation has been established (covered later) At day 22, the cranial 2/3 of the neural tube forms the brain, caudal 1/3 of the neural tube will form the spinal cord ▪ The neural folds fuse at the level of the 5th somite, proceeds cranially and caudally  Spinal Cord Development The lateral walls of the caudal portion of the neural tube thicken until only the tiny central canal remains Ventricular zone is the first layer to develop – gives rise to all neurons and macroglia Eventually the neural tube develops into an inner ventricular zone, a medial intermediate zone, and an outer marginal zone ▪ The intermediate zone becomes populated with primordial neuroblasts derived from the ventricular zone ▪ The outer marginal zone develops into white matter tracts  Spinal Cord Development When the neuroepithelial cells cease producing neuroblasts and glioblasts, they differentiate into ependymal cells ▪ ependymal cells line the central canal of the spinal cord The alar and basal plates of the developing spinal cord are separated by a groove – the sulcus limitans ▪ Plates are formed by sites of rapid growth of the neuroepithelium Cell bodies in the alar plates form the dorsal gray horns ▪ Neurons in these horns constitute afferent, or sensory, nuclei; groups of these nuclei form the dorsal gray horns Cell bodies in the basal plates form the ventral and lateral gray horns ▪ Axons of ventral horn cells grow out of the spinal cord and form the ventral roots of the spinal nerves – these have a predominantly motor function The unipolar neurons in the spinal ganglia (dorsal root ganglia) are derived from neural crest cells ▪ These grow axons and synapse with the nuclei in the dorsal horns or travel up through the white matter to the brain (usually both) Mesenchyme surrounding the spinal cord forms the meninges Spinal Cord Development Neural Crest Cell Derivatives - the PNS Neuro- epithelium Derivatives Brain Development - Overview Fusion of the neural folds in the cranial region and closure of the rostral (anterior) neuropore form three primary brain vesicles: ▪ Forebrain (prosencephalon) ▪ Midbrain (mesencephalon) ▪ Hindbrain (rhombenceophalon) During week 5, the prosencephalon partially divides into two secondary brain vesicles ▪ Telencephalon and diencephalon By week 5, the rhombencephalon also partially divides ▪ Metencephalon and myelencephalon Brain Development - Overview Forebrain Week 5 Development As closure of the rostral (anterior) neuropore occurs (day 25), two lateral outgrowths-optic vesicles- appear one on each side of the forebrain ▪ primordia of the retinae and optic nerves A second pair of diverticula, the telencephalic vesicles, arise more dorsally and rostrally ▪ They are the primordia of the cerebral hemispheres, and their cavities become the lateral ventricles Three swellings develop in the lateral walls of the third ventricle, which later become the thalamus, hypothalamus, and the epithalamus Week 7 – sagittal section  Embryology The Early Fetal-Maternal Circulation References: The Developing Human – Clinically-Oriented Embryology BMS 150 Editors: Moore, Persaud, Torchia Week 8 Chapters 4 & 7  Early Extraembryonic Structures - Review By the end of the second week the embryo (epiblast, prior to gastrulation) is surrounded by: ▪ An amniotic cavity at the dorsal surface – the amniotic cavity becomes lined by amnioblasts Extraembryonic somatic mesoderm surrounds the amnioblasts and forms the connecting stalk ▪ The umbilical vesicle at the ventral surface – this will eventually become smaller and smaller as the embryo develops and undergoes folding The amniotic cavity and chorionic membranes get larger and larger ▪ The chorion – extraembryonic somatic mesoderm on the inside and trophoblastic cells on the outside  Early Extraembryonic Structures - Review The trophoblast consists of the cytotrophoblast and the syncytiotrophoblast ▪ The syncytiotrophoblast invades the endometrial stroma and helps induce the apoptotic death of decidual cells These decidual cells release energy-rich glycogen and lipids that can freely diffuse to (and feed) the embryo ▪ The syncytiotrophoblasts secretes hCG, which allows the ovary to continue to secrete high levels of progesterone → Prevents the endometrium (and embryo) from being lost during menstruation ▪ The cytotrophoblast begins to form primary chorionic villi that project into the lacuna The Maternal-Fetal Circulation By the 4th week, the embryo and the chorion have grown large enough that diffusion of nutrients between embryo and endometrium are inadequate for metabolic demands ▪ A circulation that exchanges between the maternal and fetal tissues is necessary ▪ The embryonic heart begins to beat at day 21 – by that stage blood vessels and red blood cells are present in the fetus, and gas/nutrient/electrolyte/waste exchange between mother and embryo increases The maternal-fetal circulation depends on: ▪ A fetal cardiovascular system ▪ Structures within the endometrium that allow exchange with the fetal cardiovascular system  Chorionic Villi Secondary villus Primary chorionic villi: present in week 2 ▪ only composed of cytotrophoblasts surrounded by a syncytiotrophoblastic shell Secondary chorionic villi: present in week 3 ▪ Extraembryonic mesenchymal core surrounded cytotrophoblastic and syncytiotrophoblastic shell Tertiary chorionic villi: present by the end of week 3 Tertiary villus ▪ Blood vessels (capillaries) within the mesenchymal core ▪ Fetal blood can now exchange substances between the maternal lacuna through the membrane formed by the tertiary villus Maternal-Fetal Circulation – Week 3 Day 16 Day 21  Chorionic villi As the villi develop, the cytotrophoblast proliferates and extends through the syncytiotrophoblast layer ▪ This forms the cytotrophoblastic shell The cytotrophoblastic shell anchors the chorionic sac and attaches it to the endometrium Anchoring villus – a villus that attaches to the endometrium via cytotrophoblastic extensions Diagram of full-term placenta, just prior to birth Development of Fetal Membranes The decidua is the endometrium in a pregnant woman – 3 separate areas: Decidua basalis – the decidua that forms the placenta ▪ Connected to the embryo by the umbilical cord (which develops from the connecting stalk) Decidua capsularis – the decidua that does not include the basalis, but is still associated with/covers the embryo Decidua parietalis – formed by the endometrium that is not part of the embryo ▪ Far from the site of implantation As the embryo develops, the villi within the capsularis deteriorate and the amniotic cavity grows larger and larger, eventually filling the uterus and contacting the decidua parietalis Development of Fetal Membranes Development of the fetal membranes, placenta, and amniotic cavity From weeks 5 - 22 Pregnant Uterus “Close-up” Approximate Age – End of Week 4 Smooth chorion = the chorionic membrane that is associated with the decidua capsularis ▪ The villi degenerate (don’t contact maternal blood) Maternal blood is found in the intervillous spaces ▪ These spaces are separated by septae Development of the Fetal Cardiovascular System As the extra-embryonic tissues develop vascular associations with the maternal decidua, the fetal cardiovascular system also develops Begins in the umbilical vesicle and neighbouring connecting stalk/chorion ▪ Arises from the extra-embryonic mesoderm, starts early in 3rd week Embryonic vessels develop from mesoderm about 2 days after the extraembryonic vessels develop Divided into vasculogenesis & angiogenesis ▪ Vasculogenesis → development of brand new blood vessels from mesoderm ▪ Angiogenesis → “sprouting” of blood vessels formed by vasculogenesis Connects blood vessels to each other  Vasculogenesis & Angiogenesis Angioblasts derived from mesoderm develop in specialized regions known as blood islands ▪ The blood islands develop lumens and become blood vessels ▪ This is vasculogenesis The angioblasts also give rise to red blood cells within and outside the embryo ▪ The blood cells are derived from the inner lining of the new vessels (endothelium) ▪ Extra-embryonically – develop from the endothelium in the allantois and the umbilical vesicle ▪ Intra-embryonically – develop from the endothelium of the dorsal aorta (see later) Vasculogenesis and Angiogenesis Within the embryo, vasculogenesis → formation of angioblastic cords ▪ Occurs in the mesenchyme during gastrulation/neurulation ▪ The cords form a pair of endocardial heart tubes anterior to the prechordal/oropharyngeal membrane ▪ The caudal head fold brings the paired heart tubes caudally, towards the umbilical vesicle ▪ The heart tubes then fuse at the end of the 3rd week to form a primordial heart tube Angiogenesis links the separate cords/blood islands together to form a linked circulatory system that allows blood flow through the embryo and the developing placenta Early embryo – 3rd week  Early Embryo – 3rd and 4th week Note that cranial folding brings the heart tube ventrally and caudally ▪ The intra-embryonic coelom near the heart tube develops into the pericardial cavity ▪ The paired heart tubes are connected with the extra- embryonic vessels once the heart starts to beat at day 21 ▪ The red blood cells develop first in the extra-embryonic vessels Allantois, umbilical vesicle vessels ▪ By the 5th week RBCs arise from the dorsal aorta  Embryonic cardiovascular system – early 4th week By day 21 or 22, the heart begins to beat ▪ Blood slowly flows through the embryonic circulation into tertiary villi  Embryonic cardiovascular system – early 4th week Key vessels: Dorsal aorta – blood to the embryo and then connects to: ▪ umbilical artery ▪ cardinal veins via the dorsal intersegmental arteries The flow from dorsal aorta to cardinal veins feeds the intraembryonic tissues  Embryonic cardiovascular system – early 4th week Key vessels: Vitelline artery and vein ▪ Blood flow through the umbilical vesicle  Embryonic cardiovascular system – early 4th week Key vessels: Umbilical vein ▪ Returns blood from tertiary villi back to the embryonic heart Folding of the embryonic heart By the 4th week, the paired heart tubes have fused, resulting in a single “ventricle” and atrium As the inflow tract – the sinus venosus – bends in a counter-clockwise direction, it brings the atria superiorly and posteriorly ▪ Completed by end of 4th week The septae and valves take longer to develop  Embryology The Oropharyngeal Apparatus References: The Developing Human – Clinically-Oriented Embryology BMS 150 Editors: Moore, Persaud, Torchia Week 10 Chapter 9 The pharyngeal arches Pharyngeal arch = a core of mesenchyme (embryonic connective tissue) covered externally by ectoderm and internally by endoderm ▪ Originally, this mesenchyme is derived from mesoderm in the third week ▪ During the fourth week, most of the mesenchyme is derived from neural crest cells that migrate into the pharyngeal arches migration of neural crest cells into the arches and their differentiation into mesenchyme produces the maxillary and mandibular prominences The pharyngeal arches A pharyngeal arch contains: ▪ A pharyngeal arch artery that arises from the truncus arteriosus of the primordial heart and passes around the primordial pharynx to enter the dorsal aorta ▪ A cartilaginous rod that forms the skeleton of the arch ▪ A muscular component that differentiates into muscles in the head and neck ▪ Sensory and motor nerves that supply the mucosa and muscles derived from the arch derived from neuroectoderm of the primordial brain. The pharyngeal arches The pharyngeal arches are the main formative elements of the face, nasal cavities, mouth, larynx, pharynx, and neck ▪ During the fifth week, the second pharyngeal arch enlarges and overgrows the third and fourth arches, forming an ectodermal depression-the cervical sinus ▪ By the end of the seventh week, the second to fourth pharyngeal grooves and the cervical sinus have disappeared, giving the neck a smooth contour. Pharyngeal grooves and pouches The primordial pharynx, derived from the foregut, widens cranially where it joins the stomodeum, and narrows caudally where it joins the esophagus The pharyngeal endoderm lines the internal aspects of the pharyngeal arches and passes into diverticula (outpouchings) = pharyngeal pouches ▪ There are four pairs of pharyngeal pouches; the fifth pair is rudimentary or absent ▪ The endoderm of the pouches contacts the ectoderm of the pharyngeal grooves and together they form s double-layered pharyngeal membrane separates the pharyngeal pouches from the pharyngeal grooves 28 days Days 33- 41 The pharyngeal apparatus The pharyngeal arches begin to develop early in the fourth week ▪ neural crest cells migrate into the ventral parts of the future head and neck regions ▪ The first pair of pharyngeal arches, the primordium of the jaws, appears as surface elevations lateral to the developing pharynx ▪ Soon other arches appear as rounded ridges on each side of the future head and neck By the end of the fourth week, four pairs of pharyngeal arches are visible externally The fifth and sixth arches are rudimentary and are not visible on the surface of the embryo The pharyngeal arches are separated from each other by the pharyngeal grooves ▪ pharyngeal grooves are also numbered in a cranial – caudal sequence Bony and cartilaginous derivatives of the pharyngeal arches The first pharyngeal arch (mandibular arch) separates into two prominences ▪ The maxillary prominence gives rise to the maxilla, zygomatic bone, and a portion of the vomer. ▪ The mandibular prominence forms the mandible The proximal mandibular prominence also forms the squamous temporal bone ▪ The first arch plays a major role in the overall formation of the face The second and third pharyngeal arches form the hyoid bone Bony and cartilaginous derivatives of the pharyngeal arches The first and second pharyngeal cartilages give rise to the ossicles of the middle ear and the styloid process of the temporal bone The fourth and sixth pharyngeal arches give rise to the laryngeal cartilage The third and fourth pharyngeal arches also eventually give rise to the epiglottis The fifth pharyngeal arch is rudimentary – nothing is derived from it, and it disappears 4 weeks fetus Muscular derivatives of the pharyngeal arches first pharyngeal arch: muscles of mastication, muscles of middle ear second pharyngeal arch: stapedius, stylohyoid, posterior belly of digastric, auricular, and muscles of facial expression third pharyngeal arch: stylopharyngeus fourth pharyngeal arch: cricothyroid, levator veli palatini, and constrictors of the pharynx sixth pharyngeal arch: intrinsic muscles of the larynx. 4 weeks fetus  Arch Nerve Muscles Bones Muscles of mastication: temporalis, Maxilla, mandible masseter, medial and lateral palatine bone, vomer Trigeminal pterygoids zygomatic bone, First (but not V1) mylohyoid, anterior belly of the squamous part of the digastric, tensor veli palatini temporal bone tensor tympani malleus, incus Muscles of facial expression Upper part of hyoid stylohyoid, posterior belly of the bone Second facial digastric Stapes stapedius Styloid process glosso- Lower part of the hyoid Third stylopharyngeus pharyngeal bone 4th – superior 4th – mostly swallowing muscles laryngeal Fourth (pharyngeal – cricothyroid, levator veli (vagus) Both contribute to the + palatini, pharyngeal constrictors) 6th – cartilages of the larynx Sixth recurrent 6th – mostly muscles of the larynx laryngeal (vagus) The pharyngeal pouches The first pharyngeal pouch expands into a tubotympanic recess ▪ The expanded distal part of this recess contacts the first pharyngeal groove → contributes to the formation of the tympanic membrane (eardrum) ▪ The cavity of the tubotympanic recess becomes the tympanic cavity (where the bones of the middle ear are found) and mastoid antrum ▪ The connection of the tubotympanic recess with the pharynx elongates and forms the pharyngotympanic tube (auditory tube, Eustachian tube) The pharyngeal pouches The second pharyngeal pouch eventually gives rise to parts of the palatine tonsils By the sixth week, the third pouch develops: ▪ Into parathyroid glands – dorsal part (inferior pair) ▪ Into a thymus – ventral part The fourth pouch also develops into parathyroids – the superior pair There are no fifth or sixth pouches 5 weeks 6 weeks 7 weeks Number Pouch Membrane Groove External Middle ear, mastoid Tympanic First auditory antrum, auditory tube membrane meatus Second Palatine tonsils - - Inferior parathyroids, Third - - thymus Fourth Superior parathyroids - - Development of the thyroid thyroid gland is the first endocrine gland to develop in the embryo It begins to form 24 days after fertilization from a median endodermal thickening in the floor of the primordial pharynx This thickening forms a small outpouching-the thyroid primordium As the embryo and tongue grow, the developing thyroid gland descends in the neck, passing ventral to the developing hyoid bone and laryngeal cartilages ▪ For a short time, the thyroid gland is connected to the tongue by a narrow tube, the thyroglossal duct ▪ By 7 weeks, the thyroid gland is usually located in its final site in the neck By this time, the thyroglossal duct usually degenerates  4, 5, & 6 weeks Last image – mature thyroid