Embryology Notes (Avi Sayag) PDF

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Embryology Avi Sayag PREFACE This book is virtually a brief and differently organized version of Medical Embryology (10th edition). However, several elaborations have been added to better clarify vague explanations, relying of other books and net sources. The superscript in some terms indicates that...

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Embryology

Avi Sayag

PREF PREFACE ACE This book is virtually a brief and differently organized version of Langman's Medical Embryology (10th edition). However, several elaborations have been added to better clarify vague explanations, relying of other books and net sources. The superscript "D" in some terms indicates that the term is explained in the attached Glossary.

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Gametes are derived from primordial germ cells (PGCs) that are formed in the epiblastD during the 2nd week and that move the wall of the yolk sac.

Fig. 1: Y Yolk olk Sac

Gametes (sperm and oocytes) contain 23 chromosomes, while the PGCs contain 46. Thus, both meiosis and mitosis occur. During the 4th week after fertilization, the PGCs migrate from the wall of the yolk sac to the developing gonads. They only arrive there by the end of the 5 th week. While migrating, PGCs undergo mitosis, which continues also when they arrive in the gonad. In preparation for fertilization, they undergo meiosis to reduce the number of chromosomes by half (= gametogenesis), and cytodifferentiati cytodifferentiation on to complete their maturation. Gametogenesis = meiosis + cytodiff cytodiffe erentiati rentiation on

Nomenclature  Germ cells that undergo meiosis to produce male gametes are termed spermatocytes.  Germ cells that undergo meiosis to produce female gametes are termed primary oocytes.

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Oogenesis It should be noted that the maturation of oocytes begins before birth and completed by the end of puberty in contrast to spermatogenesis. -

Primordial germ cells arrive in the gonad of a genetic female. PGCs differentiate into oogonium, which undergoes a number of mitotic divisions. By the end of the 4th month, oogonia are arranged in clusters surrounded by a layer of epithelial cells (= follicular cellsD). The majority of oogonia continue to divide by mitosis, but some of them arrest ‘their cell division in prophase of meiosis I and form primary oocytes. Oogonia increase rapidly in the next upcoming months of prenatal development to reach some 7 million germ cells. Cell death of both oogonia and primary oocytes begin. All surviving primary oocytes enter prophase of meiosis I (by the 7 th month). Most of them are surrounded by a layer of flat epithelial cells (= primordial follicleD).

At time of birth: -

The primary oocytes do not proceed to metaphase, but rather enter a resting state during prophase that is characterized by a lacy network of chromatin (= diplotene stageD). They remain in this stage and do not complete their meiotic division before puberty is reached, due to secretion of OMI – oocyte maturation inhibition – a small peptide secreted by follicular cells.

At puberty: -

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A pool of growing follicles is established from the supply of primordial follicles. Each month, 15-20 follicles selected from this pool begin to mature. As the primary oocyte begins to grow, surrounding follicular cells change from flat to cuboidal (= growing follic follicle le le). The epithelia of the growing follicle proliferate to produce a stratified epithelium of granulosa cells (granulosa cells + primary oocyte = primary follicle). Both components of the primary follicle ( granolusoa cells and oocytes)secrete glycoproteins on the surface of the oocyte –forming the zona pellucida. As follicles continue to grow, cells of the theca folliculiD organize into an inner and outer layer. Fluid-filled spaces appear between granulosa cells. They unite to form the antrum (from L. cavity). The follicle is then termed secondary (vesicular) follicle follicle. Granolusoa cells surrounding the oocyte remain intact and from The cumulus oophorusD.

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When the secondary follicle is mature, a surge of luteinizing hormone (LH) induces the preovulatory growth phase, and meiosis I is completed. The cell enters meiosis II, but arrests in metaphase for about 3 hours before ovulation. Meiosis II is completed only if the oocyte is fertilized.

Spermatogenesis As noted earlier, the maturation of sperm begins at puberty. -

At birth, germ cells in the male infant are in the sex cords of the testis surrounded by supporting cells, derived from the epithelium of the gland. The supporting cells become sustentacular cells (Sertoli cells). Primordial germ cells give rise to spermatogonial stem cells. Type A spermatogonia emerge from these stem cells. Spermatogonia undergo mitotic divisions. The last cell division produces type B spermatogonia. (Type B are capable of differentiation). Type B spermatogonia divide to form primary spermatocytes, which enter a prolonged prophase (22 days). Secondary spermatocytes are produced as meiosis I is completed. During meiosis II, haploid spermatids are formed. Until this point, the dividing cells are joined by cytoplasmic bridges. Spermatogonia and spermatids remain embedded in deep recesses of Sertoli cells throughout their development.

Fig. 2: Spermato Spermatogenesis genesis

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Functions of Sertoli cells: Support and protect the germ cells; Participate in their nutrition; Assist in the release of mature spermatozoa. Hormonal regulati regulation on of spermatogenesis: LH is secreted by the pituitary gland, and binds to receptors on Leydig cells. Testosterone production is then stimulated, and binds to Sertoli cells to promote spermatogenesis. FSH binds to Sertoli cells to stimulate testicular fluid production and intracellular androgen receptors. SpermiogenesisD 1. Formation of the acrosomeD; 2. Condensation of the nucleus; 3. Formation of neck, middle piece and tail; 4. Shedding of most of the cytoplasm. The entire process lasts 74 days. 300 million sperm cells are produced daily.

fig. 3: Spermiogenesis

Ovari Ovarian an Cycle -

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15-20 primary stage follicles are stimulated to grow under the influence of FSH (a gonadotropin hormone secreted by the anterior pituitary gland, following stimulation by GnRH – gonadotropin releasing hormone – secreted by the hypothalamus). Only 1 reaches maturity and discharged (the others become atretic, and are replaced by CT, forming a corpus atreti atreticum cum cum). Granulosa cells are stimulated by FSH.

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Granulosa and thecal cells produce estrogens that cause the uterine endometrium to enter the proliferative phase, thinning of the cervical mucus to allow passage of sperm, and stimulate the pituitary gland to secrete LH. A surge of LH causes elevation of concentration of maturation promoting factor, and completion of meiosis I and initiation of meiosis II is made possible; production of progesterone by follicular stromal cells; and follicular rapture and ovulation. Secondary follicle grows to a diameter of 25 mm under the influence of FSH and LH. About 3 hours before ovulation, the oocyte is arrested in the metaphase of meiosis II. In the meantime, the surface of the ovary begins to bulge and the stigma appears (an avascular spot). Collagen fibers surrounding the follicle are digested by collagenase, whose activity is increased by the LH surge. Prostaglandins levels increase (in response to LH surge) and local contractions in the ovarian walls occur. Due to these contractions, the oocyte is extruded from the ovary (= ovulation). The corona radiataD is formed. The corpus luteumD is formed under the influence of LH. The oocyte is transported to the uterine tube by rhythmical contractions of the uterine tube and by sweeping movements of the fimbriaeD. The oocyte is propelled in the uterine tube by cilia (it reaches the uterine lumen in about 3-4 days. The corpus albicansD is formed if no fertilization occurs. If the oocyte is fertilized, the corpus luteum of pregnancy D (corpus luteum graviditatis) is formed.

Fig. 4: format formation ion of corpus luteum

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Fig. 5

Fertilization -

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Occurs in the ampullary region of the uterine tube. CapacitationD of the spermatozoa Penetration of the spermatozoa through the corona radiata Acrosome reactionD and penetration of the zona pellucida by ligand ZP3 (a zona protein) The sperm cell membrane fuses with the oocyte's cell membrane. Cortical reaction and zona reaction occur (release of granules with lysosomal enzymes that render the oocyte membrane impenetrable to other spermatozoa, and the zona pellucida changes its structure to prevent sperm binding and penetration. The oocyte finishes its second meiotic division which results in a definitive oocyte and a second polar body. The chromosomes are arranged in a vesicular nucleus (female pronucleus). The egg is metabolically activated. Meanwhile, the sperm nucleus approaches the female pronucleus and becomes a male pronucleus. The tail of the spermatozoon degenerated and detaches. Each pronucleus replicates its DNA to prepare for mitosis.

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Fig. 6: F Fe e rtilizatio rtilization n

Length of pregnancy: 280 days (40 weeks) after the onset of the last normal menstrual period (LNMP), or more accurately – 266 days (38 weeks) after fertilization.

After fertilization:

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The cells undergo mitosis and become smaller with each division. These sizediminishing cells are termed blastomeresD. After the 3rd cleavage (division) the cells are more compact and held together by zonulae occludentes. This process is termed compaction. The inner segregated cells communicate via gap junctions. After 3 days of fertilization, cells of the compacted embryo divide again to form a 16-cell morulaD. The morula is composed of the inner cell mass and the outer cell mass. (The inner cell mass gives rise to tissues of the embryo proper, and the outer cell mass forms the trophoblastD (which later contributes to the placenta). The morula enters the uterine cavity. Fluids begin to penetrate through the zona pellucida into the intercellular spaces of the inner cell mass. A cavity termed blastocele is formed. The embryo is then a blastocystD. Cells of the inner mass (now termed embryoblast) are at one pole, and cells of the outer cell mass (trophoblast) are flat and form the epithelial wall of the blastocyst. The zona pellucida has disappeared by this time. Trophoblastic cells penetrate through the epithelial cells of the uterine mucosa on the 6th day.

Fig. 7: morula

Fig. 8

The uterus:

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The wall of the uterus consists of 3 layers: endometrium myometrium perimetrium

Fig. 9: the uterus and migr migration ation of the fertilized oocyte

Phases of the endometrium cy cycle: cle: follicular (proliferative) phase secretory (progestational) phase menstrual phase (only if no fertilization occurs). If the oocyte is fertilized, the secretory phase does no proceed to the menstrual phase, and implantation occurs. Then, 3 distinct layers can be recognized in the endometrium: 1. A superficial compact layer 2. An intermediate spongy layer 3. A thin basal layer If the oocyte is not fertilized, the menstrual phase begins and blood escapes from the superficial arteries. The compact and spongy layers are expelled from the uterus, and the basal layer is the only part of the endometrium that is retained. In the proliferative phase, the basal layer regenerates its own arteries and glands.

Functions of FSH Rescues 15-20 primary follicles from the pool of continuously forming primary follicles (the hormone is not necessary, but without it these primary follicles die and become atretic). Stimulates maturation of follicular (granulosa) cells surrounding the oocyte. Makes secondary follicle grow to a diameter of 25 mm in the days immediately preceding ovulation. Functions of LH

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Elevates of concentration of maturation promoting factor, and completion of meiosis I and initiation of meiosis II is made possible. Stimulates the production of progesterone by follicular stromal cells. Causes follicular rapture and ovulation. Facilitates the growth of the secondary follicle to reach a diameter of 25 mm in the days immediately preceding ovulation. Increases collagenase activity during ovulation stage, resulting in digestion of collagen fibers around the follicle. Prostaglandins increase in response to LH elevation. Formation of the corpus luteum following ovulation.

Functions of estrogeni estrogenicc hormones Cause the uterine endometrium to enter the proliferative phase in the ovarian cycle. Cause thinning of the cervical mucus to allow passage of sperm. Stimulate the pituitary gland to secrete LH. They cause the uterine mucosa to enter the proliferative stage (follicular stage).

2nd week Day 8 The blastocyst is partially embedded in the endometrium. The trophoblast has differentiated into 2 layers: the cytotrophoblast D and the syncytiotrophoblastD. The cells in the Cytotrophoblast divide and migrate into the syncytiotrophoblast. Cells of the inner cell mass differentiate into 2 layers: the hypoblast D and the epiblastD layers. These layers form a flat disc – the bilaminar germ disc. The amniotic cavity appears within the epiblast layer.

Day 9 The penetration defect in the surface epithelium of the endometrium wall is closed by fibrin coagulum. Vacuoles appear in the syncytium. 12

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Lacunar stage: the vacuoles fuse to form large lacunae. The exocoelomicD (Heuser) membrane is formed. The exocoelomicD cavity is formed (primitive yolk sac).

Day 11-12 The blastocyst is completely embedded in the endometrium. Lacunar spaces are evident in the embryonic pole. SinusoidsD are formed. The lacunae become continuous with the sinusoids, and maternal blood enters the lacunar system establishing the uteroplacental circulation. The extraembryonic mesodermD is formed. Large cavities develop in the extraembryonic mesoderm to form the extraembryonic coelom (chorionic cavity). This space surrounds the primitive yolk sac.

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The chorionic cavity surrounds the yolk sac and the amniotic cavity, except where the germ disc is connected to the trophoblast by the connecting stalk (which will later become the umbilical cord). Decidua reactionD.

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Day 13 Villous structures in the trophoblast Primary villiD are formed. Secondary yolk sc is formed (definitive yolk sac) which is much smaller than the primitive yolk sac (exocoelomic cavity). Exocoelomic cysts are formed by pinching off of portions of the exocoelomic cavity. Chorionic palateD is formed. During the 2nd week, TFs: OTX2, LIM1, HESX1 and the secreted factor cerberus are expressed to form the head (see later). Week eek 3rd W -

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The most characteristic event is the gastrulation: a crucial time in the development of multicellular animals. During gastrulation, several importance things are accomplished: The three primary germ layers are established (ectoderm, mesoderm and endoderm).

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The basic body plan is established, including the physical construction of the rudimentary primary body axes.

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As a result of the movements of gastrulation, cells are brought into new positions, allowing them to interact with cells that were initially not near them. This paves the way for inductive interactions, which are the hallmark of neurulation and organogenesis.

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A primitive streak is formed on the surface of the epiblast by the expression of nodal (a transforming growth factor). The streak reaches the primitive 14

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Avi Sayag node, which surrounds the primitive pit. The node is maintained by HNF3β, which induces specificity in the forebrain and midbrain.

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Cells of the epiblast migrate toward the streak, become flattened and detach from the epiblast to slip beneath it (= invagination D). This migration and specification is controlled by FGF8D.

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The invaginating cells displace the hypoblast to create the endoderm.

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Some invaginating cells remain in the space between the epiblast and the newly formed endoderm, and thus create the mesoderm.

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Cells remaining in the epiblast form the ectoderm.

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A number of genes regulate formation of dorsal and ventral mesoderm, and head and tail structures.

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BMP is secreted in the bilaminar disc and together with FGF, the mesoderm will be ventralized (kidneys, blood and body wall).

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TF Goosecoid activates chordin, noggin and follistatin (genes) expressed in the node. They block the activity of the BMP4 stop the mesoderm ventralization (hence, the node is the organizer).

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The cranial mesoderm is then dorsalized into notochord D, somitesD and somitomeresD.

Caudal end

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The migrating cells migrate beyond the margins of the disc and establish contact with the extraembryonic mesoderm covering the yolk sac and amnion. The prechordal plate is formed in the cephalic direction (designated 7 in the figure below). The prechordal plate is formed between the tip of the notochord (1) and the buccopharyngeal membrane (3).

Prenotochordal cells become intercalated in the hypoblast. For a short time, the midline of the embryo consists of 2 cell layers that form the notochordal plate. Cells then proliferate and detach from the endoderm to form a solid cord of cells – the definitive notochord. The cranial end forms first.

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The amniotic cavity and the yolk sac are temporarily connected by the neurenteric canal.

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The cloacal membraneD is formed at the caudal end of the embryonic disc. The allantoisD appears.

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Establishment of the body axes:

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The anteroposterior axis is signaled by cells at the anterior visceral endoderm (AVE).

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TFs: OTX2, LIM1, HESX1 and the secreted factor cerberus are expressed to form the head. These genes establish the cranial end of the embryo before gastrulation.

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Also, the craniocaudal axis is determined by the genes HOXA, HOXB, HOXC and HOXD, which act along the developing embryo in the same sequence that they occupy on the chromosome.

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BMP4 and FGF, and the BMP4 inhibitors: chordin, noggin and follistatin are responsible for the ventral-dorsal axis of the cranial mesoderm.

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Brachyury (T) gene expressed in the node, notochord precursor cells and notochord, controls the dorsal mesoderm formation in the caudal and middle regions of the embryo.

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The left-right sidedness is established and regulated by FGF8, nodal (expressed only on the left side for some reason), Lefty-2, Lefty-1, and PITX2. SHH (sonic hedgehog) represses left-sided gene expression on the right.

The left-right sidedness is summarized in the following figure:

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The following chart maps the fate of the reg...