Development of placenta 1 dr najeeb biography

EMBRYOLOGY NOTES ACKNOWLEDGEMENT This is solely a composing work. Special thanks to Dr. Najeeb & drnajeeblectures.com EMBRYOLOGY HASAN BAJWA N68 EMBRYOLOGY HASAN BAJWA N68 EMBRYOLOGY NOTES USING THIS BOOK These notes are intended to enable the students to easily learn embryology. As these are made from the lectures of Dr. Najeeb, the entire focus is on concepts. I recommend that you first see the respective lecture and then read the notes. These notes are made out of utmost sincerity since I have prepared my professional exam with these. These are comprehensive and you will not need to write anything more. All diagrams drawn in the lectures are included in this. I have spent a lot of time making these thinking it might help students in the future especially who don't want to write while listening to the lectures. I recommend these notes to my juniors of 1st-year MBBS (Especially those who find embryology difficult and not understandable). Study these after listening lectures. Then read supplements which I have made from Langman's embryology (Available on Facebook). Insha Allah, you will not miss anything and it will be a piece of cake for you. Wishing you all the best! Regards Hasan Bajwa Nishtar Medical University, Multan Session 2018-2023 (N68) EMBRYOLOGY NOTES EMBRYOLOGY HASAN BAJWA N68 To my parents and my teachers. They enabled me to be who I am with their prayers and efforts. EMBRYOLOGY NOTES EMBRYOLOGY HASAN BAJWA N68 TABLE OF CONTENTS 1 CELL CYCLE AND GENES---------------------------------------------------- 01 2 GAMETOGENESIS------------------------------------------------------------05 3 FEMALE REPRODUCTIVE CYCLE-------------------------------------------11 4 FERTILIZATION----------------------------------------------------------------17 5 DEVELOPMENT UPTO 2ND WEEK------------------------------------------22 6 DEVELOPMENT UPTO 3RD WEEK------------------------------------------27 7 CNS DEVELOPMENT---------------------------------------------------------35 8 CVS DEVELOPMENT---------------------------------------------------------42 EMBRYOLOGY HASAN BAJWA N68 CELL CYCLE & GENES INCLUDES: • Cell cycle • Detail about mitosis • Certain genes that regulate different steps during cycle • Role of these genes in cancer development 1 WHAT IS CELL CYCLE How a cell passes through different phases to divide into 2 daughter cells. Sequence of all these changes through which a cell eventually divides 2 cells is called CELL CYCLE. It has 2 parts: 1-Interphase 2-Mitosis 1.1.3 G2 Phase Cell should get ready to divide duplicated genetic material for two daughter cells. After synthesis phase, when cell is preparing itself to divide genetic material equally into 2 daughter nuclei, that preparatory phase is G2 phase. It is Post synthetic/Pre-Mitotic phase. Cell is getting ready to divide its duplicated DNA into 2 daughter nuclei. 1.1.4 M Phase Genetic material is divided and nuclear membrane is eventually dissolved and genetic material is moved to both sides of cell to go to new daughter nuclei. That phase in which nuclear duplicated material of one nucleus id under process of division for 2 daughter nuclei is called Mitotic stage/M-phase. After M-phase eventually cell has divided into: 1.1 INTERPHASE When cell gets a stimulus to divide, it will: 1- Duplicate genetic material. 2- Pass through mitosis. 3-increase its cytoplasm, proteins and organelles. First of all cell duplicates its DNA. It does not start replicating DNA directly. It has to produce a lot of proteins, enzymes, increase cytoplasm, increase organelles and replicating enzymes to be produced. 1.1.1 S Phase This is phase of DNA synthesis. DNA is synthesized in this phase. DNA has been replicated semiconservatively. Every chromosome has become double structured chromosome. 2n=4n. n=23 chromosome haploid set. 1.1.2 G1 Phase Phase before DNA synthesis is called Presynaptic/G1/Growth phase 1. First cell enters G1 and prepares itself at molecular and organelle level to synthesize DNA. Then S phase will start. 1-2 cells 2-In some cells, it may enter next cell cycle. 3-In some cells it may take rest by entering G0 phase (out of proliferative cycle. If proper stimulus given, cell may enter proliferative phase again. 1.1.4.1 Labile Cells Some tissues in which cells are multiplying continuously, do not enter G0 phase. e.g- Skin cells, GIT hematopoietic cells. cells, Bone marrow 1.1.4.2 Stable Cells Some cells, if tissue does not require more cells, enter G0 phase. Now it is housekeeping function by housekeeping genes. With stimulus these can proliferate again by exiting G0. E.g- Liver cells (if you cut liver, cells start dividing and regenerate that part), Kidney nephrons, Pancreatic cells. Page 1 of 57 CELL CYCLE & GENES 1.1.4.3 Permanent Cells Cells go into G0 phase and never come out of it and don’t multiply. For these to divide, stem cells should divide to generate these cells. Once well differentiated, and performing general and specific functions, they cannot multiply. e.g- Neuronal cells, skeletal and cardiac muscle cells. G1+S+G2=Interphase 1.1.5 Cytokinesis Not part of mitosis. But takes place during mitosis. Mitosis is about nuclear division. This is about cytoplasmic and organelle division. In this, cytoplasm and organelles divide into 2 daughter cells. EMBRYOLOGY HASAN BAJWA N68 1.2 MITOSIS Prophase➔Metaphase➔Anaphase➔Telophase 1.2.1 Before Prophase There will be G2 phase. DNA in form of loose chromatin network and centrioles may be there. 1.2.2 Prophase ➔Loose chromatin condenses because Histones get dephosphorylated➔chromosomes more clear and each is double structured. ➔Nuclear membrane starts dissolving because laminin proteins get phosphorylated by enzymes. ➔Centrioles move at two opposite poles Page 2 of 57 CELL CYCLE & GENES 1.2.3 Metaphase ➔Nuclear membrane disappeared. ➔Microtubules and mitotic spindles formed. ➔Chromosomes (double structured) arranged on equatorial plate. ➔Tubular microtubules attach on Kinetochores. 1.2.4 Anaphase ➔Double structured chromosomes break at centromere➔Two chromosomes start moving to opposite poles. EMBRYOLOGY HASAN BAJWA N68 1.2.6 What causes a cell to divide? Cell division is extremely regulated phenomenon. It has checkpoints: ➔If DNA of cell in G1 is already damaged, it should be repaired before entering S phase. Cell will be arrested at this checkpoint called G1-S checkpoint. If DNA is OK, it will be allowed to move forward. ➔G2-M Checkpoint→All DNA will be scanned to make sure no error during replication and every chromosome is duplicated exactly. If anyone missing, arrested. 1.2.5 Telophase ➔Chromatids reach at poles. ➔Nuclear membrane reappears. ➔M-Checkpoint→Make sure all DNA is properly aligned on Metaphase Plate. ➔Chromosomes decondense to chromatin. ➔Cell membrane invaginates (Cytokinesis). Page 3 of 57 CELL CYCLE & GENES EMBRYOLOGY HASAN BAJWA N68 Page 4 of 57 EMBRYOLOGY HASAN BAJWA N68 GAMETOGENESIS 1 OVERVIEW →Specialized process occurring in primordial germ cells. →It is process by which early germ cells undergo process of meiosis and cytodifferentiation eventually convert into mature gamete. 2.1 SPERMATOGENESIS / GAMETOGENESIS →Meiosis is a special type of cell division occurs in 2 stages (Meiosis1 & 2). →Germ cells undergo meiotic division. →Chromosome no. is halved in final daughter cells. So, it is also called Reduction Division. ➔N=Amount of DNA in a given cell ➔InMales→Spermatogenesis→Meiosis+Cytodiff erentiation→Mature sperm. ➔1N=23 chromosomes (single structured) ➔InFemales→oogenesis→Meiosis+Cytodifferent iation→Mature ovum. 2 MEIOSIS →Early germ cells (2)Spermatogonia. are… (1)Oogonia ➔Full set of 23 chromosomes=1n ➔n=Number of chromosomes ➔2N=23 chromosomes (double structured) ➔Primary Gamete: Pri. Spermatocyte & Pri. Oocyte. ➔Germ cells replicate DNA before entering M1. Primary gamete has double structured chromosomes but number of chromosome remains same (46) since it depends on centromere. →46 chromosomes→23 from mother and 23 from father. 2.2 DIFFERENCE BETWEEN MEIOSIS & MITOSIS e.g= Ch#1 from mother and father both & son on for all chromosomes bcz these are in homologous pairs. →Normally Paternal and Maternal origin chromosomes of a homologous pair lie randomly in nucleus. ➔No. of Chromosomes=No. of CENTROMERES. ➔GENES are sequence of nucleotides which make a specific functional RNA. Those genes that are going to perform similar functions present on homologous chromosomes at same loci and are in specific relationship with each other. These are called ALLELES of each other. Mitosis No formation of homologous pairs while replicating. Meiosis Homologous chromosomes replicate and come together & pair with each other length wise and point to point called Synapsis. No synapsis & crossing Crossing over occurs. over. Chromosomes of a homologous pair exchange alleles or blocks of genes with each other after crossing over. No chiasma formation. While separating, Chromosomes remain Page 5 of 57 EMBRYOLOGY HASAN BAJWA N68 GAMETOGENESIS No assortment. attached at cross over points and moving away from elsewhere. This is chiasma formation. random Random assortment occurs. Daughter cells have maternal or paternal chromosomes bcz they assort independently. 2.2.3 Chiasma formation 2.2.1 Synapsis 2.2.4 Random assortment 2.2.2 Crossing over →Due to crossover, Maternal chromosomes are not purely maternal but have paternal genes also (at cross over point) and vice versa. →Crossing over and random assortment of chromosomes leas to genetic variability and diversity. ➔At end of Meiosis 1 we have: (1) Secondary gamete→ Secondary spermatocyte or Secondary oocyte + 1st Polar body. ➔ Chromosomes enter Meiosis 2 without replicating DNA. In M1→Homologous chromosomes go away. Page 6 of 57 GAMETOGENESIS EMBRYOLOGY HASAN BAJWA N68 In M2→ Centromere breaks and Double structured chromosome convert to 2 single structured chromosomes. ➔End of Meiosis 2 we have→ 4 Spermatids or Ovum + 2nd polar body and 1st & 3rd polar bodies. 2.3 PURPOSE OF MEIOSIS • • • • Specialized type of cell division. Occurs in germ cells. Makes them mature germinative cells. Makes sperm in males and ova in females. Page 7 of 57 GAMETOGENESIS EMBRYOLOGY HASAN BAJWA N68 3 OOGENESIS →Formation of mature ovum from oogonia. →Starts in prenatal life→ before birth. 3.1 PRENATAL DEVELOPMENT →Most primitive germ cells→Primordial germ cells. They appear in yolk sac around 4th week of development. Keep dividing by mitosis to produce oogonia and at same time keep migrating to gonads of developing female. 3.1.1 Oogonia →Surrounded by flat epithelial cells derived from epithelium on surface of ovary. →Oogonia also divide by mitosis to produce more and more oogonia. 3.1.2 Primary Oocyte →Many oogonia enlarge in size, stop mitotic division, get ready for meiosis. These are pri. Oocytes. 3.1.3 Primordial Follicle One oogonia enlarges and rest degenerate and now one oogonium and sheath of flat epithelial cells (follicular cells). This is Primordial Follicle. →Before Pri. Oocyte starts M1, DNA replicates. i.e=Duplicated 46 chromosomes. →Primary oocytes during prophase of M1 at diplotene stage get arrested. Stop progression of M1. →Before birth, all oogonia are converted to pri. Oocytes arrested at diplotene. →At birth, no Pri. Oogonia. Instead 2Million Pri. Oocytes in diplotene. →After birth, no new formation of pri. Oocytes. ➔At birth, All pri. Oocytes are surrounded by flat epithelial cells called Primordial follicle (flat epithelial cells + Pri. Oocyte in it). Page 8 of 57 GAMETOGENESIS 3.2 AFTER BIRTH UPTO PUBERTY →Pri. Oocyte remains arrested. →Most of them degenerate. →Around puberty→40000 Primordial follicles (Pri-oocyte arrested in diplotene) present. 3.3 AT PUBERTY →Start of Menstrual cycle. →FSH stimulates Primordial follicles→Every month 5 to 15 start growing but only one matures into Graffian Follicle. EMBRYOLOGY HASAN BAJWA N68 3.3.1 Ovarian / Primary /Pre-antral follicle • Primary oocyte in diplotene stage. • Some Connective tissue(c.t) cells start differentiation from ovarian stroma around cells layer. • Oocyte secretes glycoprotein outside. Follicular cells secrete glycoprotein inside. This layer is zona pallucida between oocyte and follicular cells. →Follicular cells become cuboidal (Growing Follicle). →then multi-layered (stratified cuboidal) called Primary Follicle / Ovarian Follicle. Page 9 of 57 GAMETOGENESIS 3.3.2 Secondary / Antral / Vesicular Follicle • Follicular cells proliferate a lot. Follicles become enlarged. • From the cells fluid secreted forms fluid filled spaces between follicular cells. These fuse and form a single cavity called Antrum. • Some follicular cells remain around ovum and zona pallucida called cumulus ooforus. • C.T derived from ovarian stroma thickens, makes covering around growing follicle and is called Theca Folliculi. It starts forming at level of primary follicle. Inside part is Theca Interna (outside follicular cells) & outside part is Theca Externa. • Pri. Oocyte still arrested in diplotene stage. 3.3.3 Graffian / Mature Vesicular Follicle • Now pri. Oocyte starts growing. M1 completed and 1st polar body lies b/w zona pallucida and sec oocyte. • Sec. oocyte enters M2 as soon as it is formed. • Fully mature secondary follicle also called graffian follicle. It has sec. oocyte + 1st polar body. • 3 hours before ovulation sec. oocyte arrested at Metaphase of Meiosis 2. EMBRYOLOGY HASAN BAJWA N68 suddenly becomes reactive and completes its meiosis 2→Now it is Definitive / Fertilized ovum. ➔Male and Female pronucleus swell up and fuse to form zygote and become metabolically active. 3.3.5 Function of Theca and Granulosa cells ➔Nourishment to ovum ➔Theca cells produce product (androgens) → go to Granulosa cells → convert them to special products (estrogen) that goes to uterus and make it prepared that there are chances of conception. 3.3.6 Gametogenesis vs Meiosis Gametogenesis Meiosis Oogonia→Mature Pri-oocyte→mature egg ovum Spermatogonia→Ma Priture sperm spermatocyte→Sperm atids ➔At ovulation, ovum + some cumulus ooforus cells release and taken up by fallopian tubes. Polar body is non functional cell and eventually degenerates. ➔Remaining follicular cells and theca cells remain and convert to yellow mass called corpus luteum. ➔Cumulus ooforus cells rearrange and look like a crown called Corona Radiata. 3.3.4 Fate of Ovum ➔If fertilization does not occur→Ovum disintegrates in fallopian tube and absorbed by its epithelium. (After 24-48hrs that is life of ovum). ➔If fertilization occurs→as soon as sperm touches membrane of sec. oocyte, sec oocyte Page 10 of 57 EMBRYOLOGY HASAN BAJWA N68 FEMALE REPRODUCTIVE CYCLE Also called female monthly sexual cycle / Menstrual cycle. 2 HYPOTHALAMIC ROLE 1 HIGHER CONTROL 2.1 ARCUATE NUCLEUS →Highest center playing a role in monthly cycles is HYPOTHLAMUS. This is the commanding center. →These neurons are truly masters of female reproductive activity (with some help from preoptic nucleus) →Monthly cycle can have 4 aspects: Limbic system effects hypothalamus→Ant. Pituitary→Ovaries→Uterus (1) Hypothalamus→Hypothalamic cycle This is collection of neuronal cell bodies. →These neurons release special chemical substance called Gonadotropin hormone releasing factor (GnHRF) (2) Anterior pituitary→Pituitary cycle 2.2 GONADOTROPINS (3) Ovaries→Ovarian ➔Gonadotropins→Such hormones which have tropic action (growth action) on gonads. (4) Uterus→Uterine →These are FSH and LH. →Hypothalamus controls endocrine system. It controls all visceral, autonomic, reproductive, endocrine, sexual activities including mood. 4g in weight. 2.3 VASCULAR CONNECTION ➔Masters controlled by masters. i.e= Limbic system (part of cerebral cortex controlling emotions, mood, perceptions) controls hypothalamus 3 HOW FSH & LH WORK Takes secretions (GnHRF) of hypothalamus to Ant. Pituitary cells to secrete Gonadotropic Hormones. ➔Average length of cycle is 28 days. ➔Normal range is 21 to 35 days. ➔Cycle length caries with age also. ➔If more than 35 days→Oligomenorrhea ➔If less than 21 days→Polymenorrhea ➔Menstrual bleeding remains for almost 1→4 or 5 days in start. Page 11 of 57 EMBRYOLOGY HASAN BAJWA N68 FEMALE REPRODUCTIVE CYCLE ➔First day of menstrual bleeding is first day of cycle. ➔Each month 5→15 primordial follicles start growing automatically (stimulated by local factors) to form primary follicle. ➔In females Meiosis 1 starts before birth while in men after puberty. However, M1 is completed when primordial follicle is converted to sec. follicle. ➔5→15→all into primary follicle→some into sec. follicle→suddenly ova complete M1 and start M2. ➔FSH acts on Primary follicles. Converts it to sec. follicle and sec to graffian follicle. →Zona pellucida allows only Human Male sperms to pass through. As soon as one sperm touches ovum membrane, ovum releases substances that modify zona pellucida so that no more sperms can penetrate. →Best growing follicle will grow on its own and less grown ones still dependent on FSH die. These are Atretic Follicles. (Negative feedback). →Estrogen also suppresses LH. But at mid of cycle, unexpectedly, under estrogen, Ant. Pituitary starts producing more FSH(2 to 3x) and LH(10x). (Positive Feedback). This is LH surge. ➔LH acts on graffian follicle causing: • • Graffian follicle becomes so big that it produces elevation on surface of ovary (2→2.5cm). Due to pressure blood flow lessens here. Avascular area called Stigma. • • →If no FSH, Primary follicle degenerates. →Uterus has 3 layers: • • • Endometrium→inner most layer Myometrium→middle smooth layer Perimetrium→outside C.T • muscle →Theca and Granulosa cells produce estrogen and it prepares endometrium and thickens it. This is proliferative stage of endometrium. At this time blood is at estrogen stage and ovary at follicular stage (graffian or sec). 4 DAY 1→14 Ovary→Follicular stage. Due to more blood flow fluid inside also decreases. Destructive enzymes (collagenases destroy some collagen fibers so cover becomes weak). LH has increased pressure inside follicle and made cover weak. So, it will rupture within a few hours. Ovum, zona pellucida and corona radiata will come out. ➔Due to high FSH and LH, after ovulation, fallopian tubes (finger like processes) come near to ovary and start sweeping on ovary to find stigma and capture ovum. →Structure left behind collapses (contract). It has theca and granulosa cells. LH works on these cells as: • • • Blood levels of hormones→Estrogenic stage Endometrium→Proliferative stage ➔Estrogen also acts on hypothalamus to dec FSH secretion so FSH level decreases. Blood vessels to dilate. Theca cells release destructive enzymes (proteolytic & collagenases). • Make them swell up SER becomes too much Accumulate a lot of fat globules which means a cholesterol derived hormone is going to be made. This is Progesterone. Estrogen is still produced but Progesterone in larger amounts. These cells look yellow colored. This is Corpus Luteum. It is temporary endocrine gland in female body. It’s total life is 10→12 days Page 12 of 57 FEMALE REPRODUCTIVE CYCLE ➔Just before ovulation, estrogen is at peak and it causes cervical glands to release thin mucus (normally thick) to increase chances for sperm. ➔Progesterone will act on endometrium: • • • Arteries become coiled. More blood flow. (Vascularization) More fluid in endometrium→more edema→E.M becomes swollen, warm and gets increased capability to produce nutrition. Glands in wall become more tortuous. This is Glandular/Vascular/Secretory phase of endometrium. 4.1 IF NO FERTILIZATION EMBRYOLOGY HASAN BAJWA N68 4.2 IN NEXT CYCLE BEGINNING ➔Estrogen and progesterone low bcz of Corpus Albicans. ➔Due to this, Hypothalamus produces more releasing factor and so, more gonadotropins are produced. 4.3 IF FERTILIZATION OCCURS. Day 2 → Ovum 2 cell stage Day 3→ Morula and then enters uterus and zona pellucida breaks down and fluid (uterine milk) moves in. actually nutrition material. Fluid filled cavity is Cyst. And structure is called Blastocyst. Day5→ Finger like protrusions and with their help, blastocyst hangs with endometrium. →If no fertilization, ovum dies. It sends no signal. Endometrium keeps on preparing for 10→12 days. →After 10→12 days, Corpus luteum not received any message. So, it will start degenerating and become Corpus Albicans→Progesterone level decreases dramatically. ➔Dec. progesterone causes: • • • Vessels will undergo plasticity and shut down. So, blood flow decreases. Endometrium is ischemic. Cells start dying. Necrotic changes occur. Necrotic materials slough away→Vessels are open. Bleeding starts→Menstruation. Estrogen and progesterone go down→Ant. Pituitary starts next cycle. ➔Max bleeding time is 8days. ➔Total bleeding volume is 20→80ml. If more or less, there’s problem. Endometrium has 3 layers: 1. Basal layer→Outer 2. Glandular layer→Middle 3. Compact layer→Inner Glandular and Compact layers are called Functional layers bcz these are lost in menstruation while basal layer persists. Fingers secrete digestive enzymes and digest endometrium wherever touch it. Endometrial cells undergo digestion and release nutrition foe blastocyst while being digested. It has gone inside Endometrium. 5/6 day→start implantation. 7/8day→Complete implantation. Trophoblast area of Blastocyst sends message (special chemical substance HCG via blood) to corpus luteum that causes it to multiply. Corpus luteum becomes big and starts producing heavy amounts of estrogen and progesterone. It is corpus luteum of pregnancy. High estrogen and progesterone inhibit FSH and LH release. Page 13 of 57 FEMALE REPRODUCTIVE CYCLE HCG→Human Chorionic Gonadotropic Hormone→appears in urine→released by trophoblast area. If in urine→means pregnant. EMBRYOLOGY HASAN BAJWA N68 Baby survival depends on continuous supply of estrogen and progesterone. After some time baby develops special covering around it and placenta. Page 14 of 57 EMBRYOLOGY HASAN BAJWA N68 FEMALE REPRODUCTIVE CYCLE Placenta is endocrine gland (starts producing its own progesterone)→Estrogen progesterone inc.->baby independent→Corpus luteum degenerates (3→4months). 6) Slough off and Menstruation. During pregnancy, Estrogen and progesterone remains high. 7 FUNCTIONS OF HORMONES IN CYCLE INDIVIDUALLY ➔Ovulation always occurs 14 days prior to start of menstruation. First half of cycle is not fixed. 2nd half is fixed. 7.1 ESTROGEN 5 1ST HALF SUMMARY 1) 2) 3) 4) 5) FSH inc. Primary→secondary→graffian follicle. Estrogen inc. Endometrium→Proliferative stage. First half is: ➔FSH dependent. ➔Follicular stage of ovary. ➔Estrogenic stage hormonally. ➔Proliferative stage of endometrium. 6 ON 14TH DAY 1) 2) 3) 4) FSH and LH surge Ovulation Remaining→Corpus luteum Make endometrium more secretory and vascular. ➔If fertilized: 1) Product of conception reaches uterus and implant 2) Release HCG that ➔supports corpus luteum. ➔HCG to CNS and feels nausea. ➔HCG in urine, sign of pregnancy. 3) No next cycle. ➔If no fertilization: 1) Ovum dies 2) Corpus luteum release progesterone for 10→12days. 3) Prepare uterus 4) No HCG→Corpus luteum degenerates 5) Estrogen and Progesterone dec dramatically. 1) From sec follicle→acts on uterus endometrium and thickens it. (proliferation) 2) Acts on hypothalamus to dec FSH & LH. 3) At mid cycle→ Inc FSH & LH. 4) At peak just before ovulation, causes cervical glands to release thin mucus. 7.2 FSH 1) Pri follicle→Sec follicle→Graffian follicle 2) After ovulation, causes fallopian tube processes sweeping action along with LH. 7.3 LH 1) Causes ovulation by increasing P inside follicle and weakening its wall. 2) Acts on corpus luteum and makes it corpus luteum (fat accumulation and inc SER) and secrete progesterone. 3) After ovulation, causes fallopian tube processes sweeping action along with FSH. 7.4 PROGESTERONE 1) Prepares endometrium by vacularization, swell, warm, tortuous glands and inc nutrition. 2) Dec will cause Menstrual Discharge. 3) Maintains Pregnancy. 3→4 months by corpus luteum. Rest by placenta. 7.5 HCG 1) 2) 3) 4) To CNS→ causes Nausea To blood→urine→Sign of pregnancy Supports corpus luteum and proliferates it. Inc progesterone. Page 15 of 57 EMBRYOLOGY HASAN BAJWA N68 FERTILIZATION Process of fusion of male and female gametes. 1 DEFINITION It is a coordinated sequence of molecular and cellular processes which begins with contact of oocyte and sperm and ends with the intermingling of maternal and paternal chromosomes at metaphase of first meiotic division of zygote. ➔Zygote is a unicellular embryo. ➔Most common site of fertilization in humans in AMPULLA of Fallopian Tubes. ➔Infundibulum receives ovum. Fertilization mostly in Ampulla. Fimbriae are processes. 2 HOW GAMETES REACH AMPULLA Ovum is immotile and sperm is motile. 2.1 TRANSPORT OF OVUM ➔At time of ovulation, Graffian follicle ruptures and ovum, zona pellucida & corona radiata release on the surface of ovary, Due to inc FSH and LH. ➔Due to inc FSH and LH at ovulation, fimbriae become active and sweeping over ovary and find bulge(stigma) and pick up ovum. ➔Fallopian tubes have mucosa and cells are ciliated. Cilia produce small fluid currents and help in picking up ovum. ➔Ovum reaches ampulla and survives for 24 to 48hrs. ➔Meanwhile, it may be travelling towards uterine cavity. 2.1.1 Mechanism of transport of ovum in Uterine tube Little peristaltic movements that transport ovum through fallopian tube. 2.2 TRANSPORT OF SPERM. ➔In one ejaculate, 200-500 million sperms. (100million/ml according to Langman). ➔Semen is usually 2-6ml. 10% of it are sperms and 90% are fluids from glands. →Sperms are deposited in vagina. In semen, an enzyme is activated here that causes some part of semen to coagulate and stick to cervix so it may not drain out. This is released by seminal vesicles. Its name is Vesiculase enzyme. 2.2.1 Sperms more motile in uterus / Vagina ➔Vagina is acidic (helps to protect it from microbes). So, sperms slow down. ➔Warm uterus has alkaline environment and sperms become more motile. Sperms rapidly jump from vagina to cervix. ➔Under estrogen just before ovulation, glands in cervix release mucus that is thin, less viscid, stringy and more abundant. Normally there is mucus plug in cervix canal. This mucus is tested by doctor to check ovulation ➔Tail of sperm propels sperm through cervical canal into uterine cavity. For propulsion Energy comes from Fructose in mitochondria to make ATP. Fructose is in rich amounts in semen. Mitochondria are in middle piece of sperm. All mitochondria of spermatozoa come together and make middle piece. Mucosal folds in cervical canal→Some sperms hide here and keep sitting Page 16 of 57 EMBRYOLOGY HASAN BAJWA N68 FERTILIZATION and start moving later on. So, sometimes after some days, they are seen moving. ➔Fastest speed→ sperms reach in 5 minutes. (30 minutes acc to LANGMAN) ➔Slowest→45 LANGMAN). minutes. (6 days acc to ➔Out of 500 million, 200-500 only reach and the rest disintegrate on the way and absorbed by mucosa. ➔Tail propulsion and Contraction of smooth muscles in uterus move sperm forward. Cilia also play a minor role. ➔In semen, prostaglandins are present which stimulate contraction of uterine tube to pass them to ovum in ampulla when they reach fallopian tubes. ➔After reaching Intrauterine part of fallopian tube, they stop. ➔If ovum released, ovum and its cells (Corona Radiata) release substances that are chemoattractant. Sperms detect them and move there restarting movement. 3 CHANGES IN SPERM BEFORE FUSION Two main changes: • • Capacitation reaction. Acrosome reaction. 3.1 CAPACITATION REACTION: →Special type of conditioning of sperm within female reproductive tract→Takes about 7hrs. Page 17 of 57 EMBRYOLOGY HASAN BAJWA N68 FERTILIZATION →Only capacitated sperms pass through corona radiata. ➔Enzymes are Acrosin/Trypsin like substances or Hyaluronidases. Following changes occur: ➔Zona pellucida has ZP3 protein. It binds sperm to zona pellucida as well as induces acrosome reaction. • • Glycoproteins and seminal plasma proteins are washed off→Conditioning Cilia and enzymes of mucosa digest and clear this in uterine tube. ➔Hyaluronic acid b/w corona radiata cells keep cells together. ➔Ovum has integrins and sperm has disintegrins on membrane. Membranes lockup due to interaction of integrins and disintegrins. This ensures sperms do not fall away. ➔Capacitated sperms easily pass through corona radiata. 3.2 ACROSOMAL REACTION ➔Induced by Zona Pellucida when sperm touches it. →This reaction is about fusion of acrosomal ➔Many sperms reach zona pellucida. In Fusion b/w oocyte and sperm cell membrane, post part of head of sperm involved (head region membrane is lost in acrosome reaction). 3.3 CORTICAL & ZONA REACTION As soon as sperm membrane and ovum membrane touch each other, cortical part of ovum (has lysosomal enzymes) releases lysosomal enzymes in cortical granules that are release on surface of ovum. This is cortical reaction. These enzymes cause zona pellucida and ovum impermeable to remaining sperms. This is Zona reaction. membrane and and cell membrane at multiple points. Due to fusion holes are produced→Enzymes released out of it that digest zona pellucida. ➔Species specific receptors (on zona pellucida that allow only human male sperms to pass through) are inactivated in zona reaction. Page 18 of 57 EMBRYOLOGY HASAN BAJWA N68 FERTILIZATION ➔Reaching inside sperm will undress (leave membrane out). Only sperm goes in leaving membrane. • • • • • Tail degenerates after it gets in. M2 is completed in ovum bcz before this sperm had single structured 23 chromosomes while ovum had double structured 23 chromosomes. Almost all cytoplasm of ovum after M2 goes to ovum. Now this is definitive ovum. Cytoplasm also disappears. Pro-nuclei double their DNA. (Double structured chromosomes). Come together and fuse. 4 HOW OVUM RESPONDS IF SPERM TOUCHES OVUM AND ENTERING IT • • • Cortical & Zona reaction. Completion of M2 Metabolic activation of ovum induced by sperm. 4.1 FUSION OF NUCLEI • • When touch each other both dissolve nuclear membrane. Now we have 46 double structured chromosomes. Page 19 of 57 FERTILIZATION • • • EMBRYOLOGY HASAN BAJWA N68 Mitosis starts. In metaphase, these are rearranged on metaphase plate. Centromere breaks and two cells formed ultimately. Chromatids move opposite poles. After new nuclear membrane → called Chromosomes. 5 MAIN RESULTS OF FERTILIZATION • • • Establishment of diploid number. (2n) Determination of sex of zygote. Metabolic activation of ovum and initiation of cleavage. Page 20 of 57 DEVELOPMENT UPTO 2 ND WEEK EMBRYOLOGY HASAN BAJWA N68 As ovum is metabolically active, it will not undergo apoptosis. Fertilized ovum will undergo cleavage. Previously chromosomes were arranged on metaphase plate. Now, chromosomes start close. This is compaction. They develop electrical contacts (gap junctions) with each other bcz at multiple points membranes fuse. Metabolic products, signals, ions can go through and cells can communicate. This compact inner cell mass will make baby. Outer mass will make covering of baby and placenta. Inner cells are going to make segregating. Break at centromere longitudinally. embryo proper. Chromatids move to opposite poles. During this, cell develops deep furrow. When chromatids reach poles, furrow deepens and cell divides. Both cells have 46 double structured chromosomes. ➔Morula floats in uterine fluid for 2 days. 4th and 5th day. 1 OVERVIEW First division completes in fallopian tubes within zona pellucida. ➔Around 4th day→fluid starts going in through zona pellucida→Fluid filled cavities→join and push inner cell mass to outside. This fluid filled cavity is cyst. Cells are rapidly multiplying→Blast. This structure is hence Blastocyst. ➔Early stage embryoblast still has zona pellucida. Inner cell mass is called embryoblast now. Outer cell mass is trophoblast. ➔Zona pellucida starts degenerating. Blastocyst comes out as chicken comes out of a shell (hatch out). This is 5th day. ➔Day 1→Fertilization. ➔Day 2→After 30hrs of fertilization→2 cell stage. ➔During 2nd day→4 cell stage. ➔3rd day beginning→8 cell stage. ➔Around end of 3rd day→16 cell stage→resembles melburry→so called early morula stage. Uptill now ovum is in fallopian tube. ➔Around end of 3rd and start of 4th day→Morula will fall into uterine cavity→Morula has outer and inner cell mass→Central/inner cells come very This blastocyst has to attach to endometrium. This is about 20th day if ovulation happened at 14th day. Corpus luteum is producing progesterone. ➔Day 6→Time of implantation. At that time status of endometrium is as in table: 1st half (PreOvulation) High FSH and LH Ovary: Follicular stage Ovulation 2nd half (Post(14th day) Ovulation) FSH and LH Low FSH and surge. LH -Ovary: Luteal stage Page 21 of 57 DEVELOPMENT UPTO 2 Blood: High -estrogen Endometrium: -Proliferative Blood: High estrogen but even more Progesterone. Endometrium: Glandular and Secretory ➔Most commonly, Implantation in Anterior and Posterior wall of Uterus. Less commonly in Fundus. ➔Trophoblastic cells express special molecular hooks (Selectins) →hook with other molecules (Receptors for selectins) on surface of endometrium. Receptors are special type of sugars. Blastocyst loosely attaches with sugar molecules by Selectins. ➔Now blastocyst has to move in→ It induces programmed cell death of endometrium and will go deeper and gets nutrition from dead cells. Starts implanting in b/w Glandular structures and also gets nutrition from here. 2 DECIDUAL REACTION Happens only if implantation starts. Endometrium cells around site of implantation: • • • ND WEEK EMBRYOLOGY HASAN BAJWA N68 3 DAY 6-12     Day 6→Attachment Day 7th, 8th, 9th→Getting in Day 10th and 11th→gone deep Digested endometrium area closed by fibrous plug.  Day 12→New mucosal layer develops. 4 CHANGES IN TROPHOBLAST & EMBRYOBLAST WHILE GETTING IN ➔End of 1st week→Implantation started. ➔End of 2nd week→Completes implantation. 4.1 2ND WEEK OF DEVELOPMENT Rule of 2  Trophoblast develops 2 layers. Cytotrophoblast and Syncytiotrophoblast.  Embryoblast develops 2 layers. Epiblast and Hypoblast.  Two cavities. Amniotic cavity and Chorionic cavity.  Extracoelomic mesoderm develops 2 layers. Splanchnopleuric and Somatopleuric. Becomes polyhedral. Accumulate lot of glycogen, lipids as source of nutrition and becomes edematous. This change spreads to all endometrium. ➔Powerful attachment of Blastocyst with integrins and integrates into endometrium. ➔Fibronectins and leminins help it to migrate within endometrium and attach to it respectively. Page 22 of 57 DEVELOPMENT UPTO 2 4.2 CYTO AND SYNCYTIO? 8TH DAY 4.2.1    Cytotrophoblast Clearly defined cells. Each having membrane. Each having one nucleus. 4.2.2 Syncytiotrophoblast  These are Mitotic figures.  New cells move outward from cytotrophoblast→Loose membranes and their protoplasm fuses (syncytium).  Nuclei present but cells not visible.  Produces lot of digestive enzymes.  Develops more on embryonic pole. ➔Around 9th day→Fluid filled cavities called Lacunae form on Syncytiotrophoblast. Lacunae get connected around 10th and 11th day. ➔While moving in, Syncytiotrophoblast may digest dome of capillaries (sinusoids)→Blood may come into lacunae→Some lacunae connected to venules so blood seeps in and out. This is establishment of Uteroplacental th th circulation→Around 11 and 12 day. ➔So, If around 13th day, area of digested endometrium is not plugged, little blood may drain. This is 27th day, Time of menstruation also. It may result in wrong calculation of expected date of delivery. ND WEEK EMBRYOLOGY HASAN BAJWA N68 ➔Around 14th day→Cytotrophoblastic cells make columns of cells moving into Syncytiotrophoblast. These are called Primary Villi. 4.3 EMBRYOBLAST ➔Cells of embryoblast facing cystic cavity make layer of cells. These cells make cuboidal cell layer facing cavity. These are called HYPOBLAST. ➔Above, Cells make columnar cell layer called EPIBLAST. ➔Some cells above it also. They develop fluid filled cavities→Later fuse to form Amniotic cavity and layer pushed up→Amnioblast. Columnar cells facing newly developed cavity. Cuboidal cells facing Blastocystic cavity. Amniotic cavity is lined by Amnioblast and Epiblast. ➔Hypoblast cells move down and enclose a cavity called Primary yolk sac. In b/w Primary yolk sac and amniotic cavity, we have Bilaminar germ disc having Epiblast and Hypoblast. ➔Downwards, Hypoblastic cells start secreting Connective tissue between yolk sac and cytotrophoblast. This connective tissue moves up as well between Amnioblast and Cytotrophoblast. Since this C.T is outside embryo (Proper germ layer), this is called extraembryonic mesoderm. Page 23 of 57 DEVELOPMENT UPTO 2 ND WEEK EMBRYOLOGY HASAN BAJWA N68 Page 24 of 57 DEVELOPMENT UPTO 2 ND WEEK EMBRYOLOGY HASAN BAJWA N68 Cytotrophoblast+Syncytiotrophoblast+Somatopl euric layer=Chorionic Plate ➔Real baby comes out of 2 layers (Bilaminar disc). ➔Connected outside by Connecting Stalk which develops into umbilical cord in future. Also connected to chorionic cavity by same stalk. ➔Syncytiotrophoblast produces hCG. ➔Sec Yolk sac disappears lateron. Page 25 of 57 DEVELOPMENT UPTO 3 In the beginning of 3rd week of development, Bilaminar disc→Trilaminar disc. Gastrulation EMBRYOLOGY HASAN BAJWA N68 WEEK 1.1.1 Purpose of groove ➔Cells from epiblast start proliferating and migrating to primitive groove/streak. Why? 1 GASTRULATION Bilaminar embryonic disc RD Trilaminar embryonic disc ➔Embryo having 3 layers is called Gastrula. ➔Bilaminar disc formed during 2nd week. (bi for 2) ➔Trilaminar germ disc formed during 3rd week. (tri for 3). Looking embryo/disc from above we see: ➔We see very flat disc in the beginning. An area of thickness called prechordal plate at cephalic end. This is area where both layers are very close to each other. ➔From caudal to cephalic end, cells start proliferating along central axis and a longitudinal streak (Line) appears. This is Primitive streak. Its anterior part is more wide→Primitive Node. Cells from center of Primitive streak and Primitive node disappear. Line within primitive streak where cells are deficient is called Primitive groove. Central depression in primitive node is called Primitive pit. ➔Primitive streak and node cells start producing chemical substances (Fibroblast growth factor 8) (a protein) that attract cells to it. This substance moves laterally and neighboring cells proliferate rapidly and then migrate. Hypothalamic cells held by E-Cadherins(Sticky). FGF8 reduces reduces concentration of E-Cadherins to make migration of cells possible. ➔Cells moving towards groove then move down through groove→After coming down they become flask shaped cells and move laterally and forwards to cephalic end→Mix with hypoblast cells→Hypoblast cells start degenerating and these cells take place of hypoblast→Hypoblast replaced by a new layer called Endoderm. Endoderm derived from Epiblast. ➔Once it is made, another generation of cells start migrating in the same way→Coming down→spread to place in b/w epiblast and endoderm→this is Mesoderm. This is present everywhere b/w ecto and endoderm except 3 places: • • • Prechordal plate. Posterior/caudal part of disc. Buccopharyngeal membrane. Page 26 of 57 DEVELOPMENT UPTO 3 Mesoderm is derived from epiblast. ➔Layer of remaining part of epiblast is ectoderm. Remaining layer of Epiblast which has already made endoderm and mesoderm. Ectoderm is derived from epiblast. 1.1.2 Cells moving through Primitive Node ➔Primitive streak present only on posterior aspect (caudal) of plate. Because cells are moving forward also, so, caudal end area around primitive streak is truly loosing cells and cephalic end area ahead of primitive streak truly gaining the cells→Caudal end becomes narrow and Cephalic end becomes broad with the passage of time. Initially almost round then longitudinal and then like a sleeper. ➔From this circular pit cells will move in and migrate down and forward because below is hypoblast. As they go down circularly, a tube like arrangement is formed b/w epi and hypoblast. ➔These cells in tube arrangement move from primitive node upto prechordal plate between epiblast and endoderm. This tube is Notochordal tube / canal. Derived from primitive pit. This tube acts as central axis of body/ embryo. Vertebra will develop from it. Longitudinal section as shown in 2nd row in above figure. RD WEEK EMBRYOLOGY HASAN BAJWA N68 Mesoderm can be seen absent in 3 areas described earlier. These are: 1. Cloacal plate & Caudal end→Ecto and Endo held together. 2. Buccopharyngeal membrane (Future mouth area) & prechordal plate→Just cephalic to prechordal plate. 3. Where something else is present in between→ Notochordal tube. ➔Notochordal tube is opening above into amniotic fluid. With passage of time, floor of tube fuses with endoderm and both disintegrate. Temporarily, fluid of amniotic cavity gets connected with yolk sac. This is established through Neuroenteric Canal. Why this canal is called so? Because later on, area above→Nervous system develops from it. Area below→ GIT develops from it. Canal is from part of disc going to develop nervous system to part of disc going to develop GIT. Roof of tube in contact with Epiblast. Transverse section (Figure ahead) After loosing floor, tube changes to plate intercalated with endoderm (roof of yolk sac). Neuroenteric canal will disappear. ➔Notochordal plate detaches endoderm and proliferates a lot and make solid mass of cells. Page 27 of 57 DEVELOPMENT UPTO 3 ➔Endoderm will proliferate also and fill gap. Now, this solid rod is definitive notochord. RD WEEK EMBRYOLOGY HASAN BAJWA N68 Ectoderm→Skin Mesoderm→ Muscles, Urogenital system, Bones Role of notochord: • • • Plays very important role in development of nervous system. Causes cells in ectoderm to proliferate by producing products. These cells will form Neural plate. Involved in Paraxial mesoderm formation. In center of Intervertebral disc, there is nucleus pulposus. It is remanent of notochord in adults. 2 IN THE END OF 3RD WEEK • • A trilaminar disc formed. Has endoderm, mesoderm (except 3 places) and ectoderm. Endoderm→GIT Notochord→Causes development of vertebral column and spinal cord around it. ➔From ectoderm, we pull out material for limbs (Ectodermal skin, nails, hair) and mesoderm (Muscles, ligaments, tendons) also goes there. In the end of 3rd week and beginning of 4th week, Gastrulation is Completed. When gastrulation is completed, Primitive streak disappears. Disc will roll up→Folds go laterally→Ends fuse. Page 28 of 57 DEVELOPMENT UPTO 3 RD WEEK EMBRYOLOGY HASAN BAJWA N68 Page 29 of 57 DEVELOPMENT UPTO 3 3 PROBLEMS OCCURING GASTRULATION IN Damage to the embryo during its early development is called Teratogenesis. Substances that produce teratogenesis are called teratogenic substances. Many toxins and drugs are teratogenic. e.g= High Alcohol intake at time of development of trilaminar germ disc damages development of embryonic tissue. Female may be unaware of pregnancy or think that periods are delayed and not take precautions. If she takes high doze of alcohol, it will damage trilaminar disc. By now, trilaminar disc is programmed about what tissues will be made from three layers. ➔2rd-8th week most dangerous time because layers will start forming tissues and organ systems. Upto 8th week, most of body tissues and organ RD WEEK EMBRYOLOGY HASAN BAJWA N68 systems are made. After this, further is usually maturity of organ system. At this stage (2-8week), a little damage to embryo may produce a very big damage to developing system. 3.1 HOLOPROSENCEPHALY ➔Alcohol is highly lipid soluble. It will be rapidly absorbed in GIT and go into the blood. Any substance that is highly lipid soluble will efficiently cross placenta. Placenta is not established yet. So, we say it product of conception. ➔Alcohol→GIT→absorb→Dissolve into blood→dissolve into biological barriers and cross them to reach upto product of conception→Destroy cells of midline from prechordal plate and anteriorly (to cephalic end) because these cells are very sensitive to high doses of alcohol. They also destroy cells in notochordal tube area→ This area folds lateron and forms front of head and neck. So, there can be: Page 30 of 57 DEVELOPMENT UPTO 3 • • Eyes may be abnormal→Central/midline structures may underdevelop and eyes more near to each other→Hypotelorism. Underdevelopment of forebrain specially central area. In CNS there are ventricles (CSF produced). From lateral ventricle, fluid to central area (3rd vent.) and then a duct and then into 4th vent. Central area underdeveloped so, both laeral ventricles more near→Fuse. WHOLE THIS COMPLICATION HOLOPROSENCEPHALY. IS CALLED RD WEEK EMBRYOLOGY HASAN BAJWA N68 1. Lower limbs ma not form properly and may fuse. (Hypoplasia of lower limbs). 2. Abnormal vertebral column (lumbar and Sacral region) →caudal intermediate mesoderm in this area also less so structures from it also abnormal→Urogenital system (Many parts of this system derived from intermediate mesoderm. 3. Renal agenesis 4. Genital abnormalities 5. Imperforate anus. The is no perforation of anus. 3.2 SIRENOMELIA / CAUDAL DYSGENESIS THIS IS CAUDAL DYSGENESIS OR SIRENOMELIA. ➔If a drug/toxin causes damage to posterior end (caudal end)→Caudal area does not develop well→Caudal dysgenesis. 3.3 CILIOPATHIES / SITUS INVERSUS / KARTAGENER'S SYNDROME Mostly occurs in children of those females who have diabetes mellitus. ➔There is mesoderm. underdevelopment 3.2.1 Problems of caudal ➔During formation of gastrula, gene is damaged that is encoding for dynins. ➔Cilia on ventral aspect of endoderm alter concentration of certain substances (produced by disc) →which determine which side of fetus will be right or left and also play a role in pattern development on left/right side of body. Page 31 of 57 DEVELOPMENT UPTO 3 RD WEEK EMBRYOLOGY HASAN BAJWA N68 ➔Endoderm is on visceral side. Here, viscera of thorax and abdomen will form. Abnormal dilation of bronchial passages and full of infection→Bronchiactitis. Cephalically→Heart, Respiratory system. ➔Sperms→ non motile→Male infertility. Caudally → GIT along liver/Pancreas/Other structures in abdomen. Situs Inversus with all additional problems is called Kartagener’s Syndrome. ➔Rarely, heart lies on left side called dextrocardia. Normally heart on left along with spleen and stomach. Liver on right side. ➔A patient may have all organs on opposite sides in abdomen called Situs Inversus → Site of viscera are transpositioned in thorax and abdomen. Patient may have no problem. 3.3.1 What is the Problem? ➔When patient in stage of development of gastrula (Product of conception in gastrulation at trilaminar disc stage). ➔Additional problems include: 1. Chronic sinusitis 2. Bronchiactitis 3. Male infertility (Male specific) Most of structures in adult body with cilia like structures, their cilia will dysfunction. Cilia have special proteins DYNINS that are abnormal in these (genetic problem). This may also lead to situs inversus. ➔Paranasal sinuses→Cilia→force mucus to go to nose. If cilia not working well, mucus collects here. Bacteria settle and proliferate and cause chronic sinusitis. 80% patients have no problem. In these cases we say this is Primary ciliary dyskinesia. 20% have additional problems. Cilia have dysfunctioned during development. ➔Cilia in respiratory passages→ some cells produce mucus here→cilia push mucus to pharynx and then to stomach/esophagus. If not working well, mucus accumulates and bacteria settle→Infection→bronchial walls weak. So, Page 32 of 57 DEVELOPMENT UPTO 3 RD WEEK EMBRYOLOGY HASAN BAJWA N68 Page 33 of 57 NERVOUS SYSTEM DEVELOP. EMBRYOLOGY HASAN BAJWA N68 1 INTRODUCTION ➔Mid-cycle→ LH surge→ Ovulation→ ampulla→ Fertilization→ definitive/Fertilized ovum (cell memb, zona pellucida and corona radiata)→ Meiosis-2 completed→ Zygote→ Blastula→ Morula→ Blastocyst→ Embryoblast and Trophoblast→ villi at embryonic pole→Cyto and cyncytiotrophoblast. ➔Almost at 1 week→ villi→ destructive enzymes→ dissolve endometrium→ start implantation→ uterus secretory/ luteal stage→ implants in superior and posterior wall mostly. 10→12 days life of corpus luteum→ hCG by cytotrophoblast→ corpus luteum of pregnancy (also called Corpus luteum gravidarium)→ keeps endometrium secretory. ➔At 2nd week: • • • • • • • From center to cephalic & caudal→ some cells separate from tube→ neural crest cells Anterior & posterior neuropores close at 25th and 27th day respectively. Notochord: 1. Produces substances that develop neural tube. 2. Major role in development of CNS. 3. Ramanant as Nucleus pulposus in intervertebral disc. hCG detectable in urine after 10 days. Bilaminar disc formation. Amniotic cavity and yolk sac. Epiblast and hypoblast tightly held at prechordal plate. A site of future mouth of baby. ➔3rd week • • • • • Primitive streak and node→ gastrulation→ 3layers. Trilaminar disc formation. Ectoderm, endoderm and mesoderm. Notochord formation between ecto and endoderm form primitive pit upto prechordal plate at mesoderm area since there mesoderm is absent. Notochord releases chemicals→ ectoderm rapidly proliferates→ Additional layer of cells→ longitudinal thickness→ Neural Plate→ Starts folding and depressing down→ edges raising→ center depressing→ neural folds and grooves→ folds fuse eventually. ➔At 25/27 day there should be sufficient folic acid in blood. This time first period in missed usually. If Page 34 of 57 EMBRYOLOGY HASAN BAJWA N68 NERVOUS SYSTEM DEVELOP. anterior neuropore does not close properly→ Anencephaly occurs: • • • • Rudimentary brain stem. Upper part of CNS not formed. Baby not capable of extrauterine survival. Born dead or dies after birth. If posterior neuropore does not close in time→ problems occur in lower back area (e.g= Spina Bifida). 2 NEURAL TUBE DERIVATIVES ➔At cephalic end of tube→ 3 swellings called Primary Vesicles appear→ Make future brain. 1. Prosencephalon (Forebrain). 2. Mesencephalon (Midbrain). 3. Rhombencephalon (Hind Brain). This tube is having CSF filled cavity throughout. In upper part, it will make brain ventricles. Lamina Page 35 of 57 NERVOUS SYSTEM DEVELOP. EMBRYOLOGY HASAN BAJWA N68 terminalis→ structure in adult brain here anterior neuropore closed. 2.3.2 Myelencephalon → Medulla Oblongata. 2.1 PROSENCEPHALON 2.4 TELENCEPHALON →very rapidly growing except mid portion that is slow. So, prosencephalon divides into 2 vesicles telencephalon and diencephalon. → rapidly developing. It has one area underdeveloped located above diencephalon called Insula. Rest of telencephalon grows around INSULA: Telescopes converging on Diana Princess. 2.2 MESENCEPHALON →remains same. • • • • Forward→ Frontal lobe Upward→ Parietal lobe Backward→ occipital lobe Downward and turns→ temporal lobe 2.3 RHOMBENCEPHALON →2 vesicles: 1. Metencephalon at cephalic end. 2. Myelencephalon at caudal end. 2.3.1 From posterior side of metencephalon → special plate develops→ structures develop backward→ cerebellum hemispheres develop. What remains anteriorly is Pons. 2.5 DIENCEPHALON is thalamus, hypothalamus and other structures around it. Page 36 of 57 NERVOUS SYSTEM DEVELOP. EMBRYOLOGY HASAN BAJWA N68 2.6 CNS CORRELATES ➔From nasopharynx→ epithelial cells grow up and back→ ruthke,s pouch→ convert into hypophysis (Anterior pituitary). ➔Retina, uveal tract (choroid, ciliary body and iris) of eye, optic nerve, chiasma, optic tract all develop from diencephalon. ➔Optic nerve not actually a nerve but a CNS tract derived from diencephalon. ➔Lateral geniculate body on thalamus→here optic tract ends. sides of ➔Anterior pituitary does not develop from neural ectoderm. Page 37 of 57 NERVOUS SYSTEM DEVELOP. 3 SPINAL CORD Cross section: 3.1 GREY MATTER ➔Layer of cells multiplying (neuroblasts) develop on posterolateral sides→ ALAR (means ear) plates→ sensory grey matter. ➔Anterolateral development→ basal plates→ play role in motor system→ motor grey matter. ➔Grey matter from center to anterolateral and posterolateral sides. • • • EMBRYOLOGY HASAN BAJWA N68 Go upward→ tracts (Dorsal). Laterally and up→ lateral tracts. Cross to opposite side anteriorly and go up→ Anterior tracts. So, we get: 1. 2. 3. 4. 5. Dorsal column Lateral column Anterior column Anterior spinal fissure Dorsal sulcus ➔Fluid filed cavity→ cells proliferate→ grey matter→ basal and alar plate→ motor and sensory grey matter→ Motor (to tissues) and sensory (projections to cns. Actually receiving from ganglion.) ➔Dorsal Root Ganglion: →peripheral (skin, joints, proprioception)→ dorsal root → directly back and go up and relay at upper level OR relay here and n2d order neuron cross and go lateral or to anterior side. 4 RHOMBENCEPHALON Going up→ spinal cord converts into pons and medulla. Arrangement throughout brainstem: 3.2 WHITE MATTER Motor grey matter→ center ➔From anterolateral sides→ Fibers come out from tails of cells→ motor fibers→ eventually in motor nerves. Sensory grey matter→ sides ➔Neural crest cells proliferate→ dorsal root ganglion→ some connection to periphery and some to sensory side. Neurons in DRG initially bipolar→ fuse→ unipolar→ one central process to center and one peripheral process to periphery. ➔some neural crest cells form cranial nerve ganglia and peripheral spinal nerve ganglia. ➔top of brain→ motor fibers coming down→ crossing the medulla→ major sensory fibers will cross at different levels in brainstem speccialyy medulla→ so motor and sensory horns fragmented. These fragments→ nuclei (may be motor or sensory). ➔Hypoglossal nucleus→ motor nucleus→ basal plate. Trigeminal sensory nucleus→ ALAR plate. ➔Posterolateral side fibers: Page 38 of 57 NERVOUS SYSTEM DEVELOP. EMBRYOLOGY HASAN BAJWA N68 Page 39 of 57 EMBRYOLOGY HASAN BAJWA N68 NERVOUS SYSTEM DEVELOP. 5 NEURAL CREST CELLS DERIVATIVES 5.1 NAJEEB’S WAY • • • • • • • • • • • Initially on sides of neural tube. Spread throughout ectoderm→ skin→ melanocytes. Some scatter around neural tube and its derivatives (around all CNS)→ Pia and arachnoid matter (leptomeninges). Dura matter from mesoderm. Some made aggregates around spinal cord→ ganglia (sensory or autonomic, cranial or spinal) Bones in neurocranium Sympathetic ganglia put together and lost axons→ gland--. Adrenal medulla. Parafollicular C-cells in thyroid gland (Produce calcitonin). Teeth→ odontoblasts Conotruncal cushions and aorticopulmonary septum Schwan’s cells (PNS). Mesenchyme of pharyngeal arches. • • • • • • Respiratory system structures Digestive system structures Thyroid gland Parathyroid gland Tonsils Thymus ➔in Abdomen: • • • 5.2.3 • • • • Liver Pancreas Lining of urinary bladder Mesoderm Muscles→ smooth, cardiac, skeletal. Vessels→ CVS, lymphatic. Reproductive→ testes, ovaries, etc. Urinary system→ bladder etc. 5.2 SELFLESS MEDICOSE METHOD 5.2.1 Ectoderm ➔Outside structures: • • • • • • • • Skin/epidermis Hair Eyes Nose Ears Nails Teeth enamel Mammary glands ➔3 inside structures: • • • CNS PNS Pituitary gland 5.2.2 Endoderm ➔in the NECK: Page 40 of 57 CARDIOVASCULAR SYSTEM DEV EMBRYOLOGY HASAN BAJWA N68 1. Outer cells→ called angioblasts→ make endothelial cells. 2. Inner cells→ separate→ blood cells. 1 OVERVIEW 1. Arterial system 2. Venous system 3. Fetal circulation ➔CVS develops from→ mesoderm→ Intraembryonic and extraembryonic (specially connecting stalk mesoderm). ➔Extraembryonic mesoderm present/consist of: 1. Mesoderm in connecting stalk 2. Around yolk sac and amniotic cavity 3. Chorionic layer ➔Multiple islands of cells communicate (grow to each other and become continuous) then canalize by disintegration→ blood vessels. This is Vasculogenesis. ➔in Extraembryonic mesoderm: 1. Blood vessels mainly in connecting stalk 2. Some Around yolk sac 3. Some In chorionic mesoderm ➔Major role in CVS development→ splanchnopleuric intraembryonic mesoderm. Other parts also involved→ somites, intermediate mesoderm, somatopleuric mesoderm. ➔Make vessels→ 2 ways→ 1. Vasculogenesis 2. Sprouting of previous vessels. ➔Angiogenesis→ from wall of these vessels→ cells proliferate and form cords→ central walls degenerate and branches form. 2 ARTERIAL SYSTEM 1. Pharyngeal arches 2. Rest of body 2.1 PHARYNGEAL ARCHES How mesenchymal cells make vascular system & blood? ➔Mesodermal differentiate: cells proliferate→ Masses→ ➔Around pharynx→ mesoderm→ proliferates→ moves forward and down→ pharyngeal arches. Multiple develop bilaterally. ➔Proliferated solid mass of mesoderm that grows anterolateral to pharynx and moves forward and downward as paired structures Page 41 of 57 CARDIOVASCULAR SYSTEM DEV (Right & Left). Each has its own nerve and arterial supply. ➔Heart developing in neck ventrally→ this is Truncus Arteriosus. Distal part of truncus is called Aortic sac. EMBRYOLOGY HASAN BAJWA N68 this arterial system descends down, it pulls this nerve down. Larynx is up and nerve going down which was originally straight. But still connected to larynx but course is reverse→ Recurrent laryngeal nerve. ➔Dorsally→ 2 dorsal aortae. Aortic sac→ vessels sprout to pharyngeal arches and fuse with dorsal aorta of respective side. 5th pharyngeal arch→ vessel does not develop or regresses very rapidly. ➔Every arch having its own artery (Paired). Ventrally→ Aortic sac. Dorsally→ Dorsal aorta. These vessels as paired structures connecting aortic sac with dorsal aorta are called Pharyngeal or Aortic arches. ➢ First pharyngeal/ aortic arch ramanant→ Maxillary artery. ➢ 2nd→ stapedial artery (Stapes bone relation). ➢ 3rd→ carotid system (Common, internal and external). ➢ 4th→ ➔Aorta of one side except its proximal part and proximal part of pulmonary artery (these are from truncus arteriosus). ➔Subclavian artery. ➢ 6th→ vessels related to lungs. (Pulmonary artery) ➔from 6th arch→ ductus arteriosus. So, after birth→ ligamentum arteriosum. (left side). On right side→ 6th degenerates so nerve hooks around 4th. From 4th→ right subclavian artery. So recurrent laryngeal nerve hooks around right subclavian artery on right side and ligamentum arteriosum on left side. First make sexy steps then call for aortic arch and sleep with lungs ➔Sometimes anomaly. Right side dorsal aorta does not regress and two aortic arches form. These enclose esophagus and trachea causing dysphagia and dyspnea. ➔Right side→ distal part of 6th arch degenerates. Left side→ continue as left pulmonary artery and ductus arteriosus. ➔At T4 Dorsal aortae fuse and form dorsal aorta. ➔Initially, dorsal aortae around respiratory and digestive system. ➔Vagus nerve gives branch that is below and behind 6th arch. Going to developing larynx. When Page 42 of 57 CARDIOVASCULAR SYSTEM DEV 2.1.1 COARCTATION OF AORTA • just before/ just after ductus arteriosus • distal to origin of left subclavian artery→ aorta may become narrow or constricted. • Congenital anomaly • Problem primarily with tunica media. • Smooth muscles in ductus arteriosus are transferred to smooth muscle layer of aorta. Since ductus arteriosus closes at high O2, this may also close causing constriction. • Primarily, media of aorta constrict. • Secondarily, intima inside also proliferates→ more constriction. • Before duct→ pre-ductal coarctation. After duct→ post-ductal coarctation (Mostly). • Associated with cardiac abnormalities, turner syndrome. More common in boys. EMBRYOLOGY HASAN BAJWA N68 2.1.1.1 PRE DUCTAL 1. Left ventricle to aorta→ blood cannot go properly 2. Arch and its branches→ increased blood pressure and flow. 3. Reduced blood downstream→ reduced oxygen. 4. At reduced oxygen→ductus arteriosus may remain open. Blood moves from ➔Effects→ blood cannot go down. Page 43 of 57 CARDIOVASCULAR SYSTEM DEV pulmonary artery to aorta distal to obstruction. 2.1.1.2 Post ductal: 1. Bp high as before in arch and branches. 2. But ductus arteriosus closes because O2 is good 3. Downstream→very reduced blood flow and bp. 4. So blood takes collateral path. Blood→ aorta→ left subclavian→ internal thoracic (dilates)→ intercostal arteries (reverse direction)→ distal part of aorta. Intercostal arteries→ pulsations→ damage ribs development→ notched ribs. 5. May also go via periscapular anastomoses because it is also connected with intercostal arteries. 6. Inc. bp in upper limbs. 7. Dec. bp in lower limbs. 8. Palpate radial and femoral pulse simultaneously→ little delay in femoral pulse. 9. Auscultate chest→bruit is heard. Because collateral vessels have increased blood pressure audible. Abnormal audible sound heard due to abnormally high blood flow through arteries is called bruit. 10. Treatment→ surgically removed. 11. Increased risk of stroke because increased bp to head may lead to burst of small vessels in CNS. 12. Abnormal blood flow→ infection→ endocarditis. EMBRYOLOGY HASAN BAJWA N68 ➔Lateral branches→ kidneys (renal vessels). Renal vessels also supply suprarenal glands and gonads because gonads originally develop on sides of aorta in abdominal cavity. Later on ovaries descend to pelvis and testis to scrotum. ➔Ventral branches→ Vitelline arteries originally. Because in embryo→ front→ yolk sac and git. And aorta at the back. 1. They have many branches looking like sun. so called sunciliac (actually CILIAC) artery→ foregut. 2. Superior mesenteric→ upper git artery→ midgut. 3. Inferior mesenteric→ lower git artery→ hind gut. 4. Some ventral branches also come down→ 2 arteries→ move forward→ upward→ enter umbilical cord→ umbilical arteries. 5. When aorta develops in lower part→ divides→ two→ common iliac arteries→ external and internal iliac arteries. 1,2,3 are derivatives of vitelline arteries. 2.2 DEVELOPMENT OF OTHER ARTERIES ➔initially around 4th and 5th week→ 2 dorsal aortae. Eventually fused→ one dorsal aorta. From dorsal aorta→ branches→ posterolateral branches and lateral branches. 2.2.1 1. 2. 3. 4. 5. Posterolateral Branches: To upper limbs Intercostal arteries Lumbar Sacral Lower limb ➔From aorta to yolk sac→ vitelline artery→ Loose connection with aorta→ move down in origin→ internal iliac artery. Page 44 of 57 CARDIOVASCULAR SYSTEM DEV EMBRYOLOGY HASAN BAJWA N68 In developing heart, venous input system is sinus venosus. Initially during 4th and 5th week, all 3 systems go to sinus venosus. CUVVUC ➔Cardinal veins→ draining Anterior Cardinal veins upper body→ ➔cardinal veins→ draining lower part of body→ Posterior cardinal veins. Both come together before draining in sinus venosus to form common cardinal vein (for a short distance). ➔Originally, umbilical arteries→ from aorta. With development→ Origin down→ separate and come down as internal iliac. Connected with villus vasculature in placenta. In adults, umbilical arteries degenerate, close and become fibrotic→ called Medial umbilical ligament. ➔Adult remnants of umbilical arteries: 1. Going inside→internal iliac 2. Just above urinary bladder→ vesicle artery. 3. Remaining→ fibrotic→ MUL→ just inside anterior abdominal wall. 3 VENOUS SYSTEM 3 venous systems developing. 1. Which is draining yolk sac→ vitelline veins→ 2 (right and left) 2. Which is bringing blood from placenta to embryo or fetus→ umbilical venous system. 3. Head & neck, upper limb and other developing body→ cardinal venous system (right and left). Mostly, right sided system develops more than left side (regresses) because caval system on right side. ➔As further development→ system should modify such that it should drain on right side and sinus venosus→ originally symmetrical→ becomes asymmetrical and bilateral to unilateral. With time, left horn of sinus venosus→ regresses and change. Somehow, most of venous system connects to right side. 3.1 VITELLINE SYSTEM ➔Septum transversum, GIT also developing. Initially, 2 umbilical veins. But later on, only one. Page 45 of 57 CARDIOVASCULAR SYSTEM DEV EMBRYOLOGY HASAN BAJWA N68 ➔Two vitelline veins coming from yolk sac→ go near duodenum/ developing git and around duodenum→ Make a plexus. 3.2 UMBILICAL VEINS ➔On the way to sinus venosus→ pass through septum transversum. (here liver bud comes and develops). Liver bud becomes so large that vitelline vein has to pass through liver. ➔As liver enlarges→ right and left umbilical veins also have to connect to liver. ➔While passing through liver→ break down into smaller vessels→ sinusoids (wide bore capillaries). Recollect and go out as hepatocardiac channels (R & L)→ carry from liver to heart. ➔Modification starts→ left side→ degenerates or fuses with right vitelline. So, left vitelline largens→ hepatic portal vein. Why Portal? 3 derivatives of vitelline arteries come to GIT. Recollect into portal system. This again breaks up into microcirculation. So, it is connecting two microcirculations→ portal. ➔initially, 2 umbilical veins→ bringing blood to sinus venosus. Also break into sinusoids. So, microcirculation of liver is derived from 2 • • Mainly, vitelline veins Partly, umbilical veins Recollect and mix with sinusoids of vitelline veins. By 2nd month of pregnancy→ all right umbilical vein, except a little part of sinusoids, degenerates. ➔Left umbilical vein→ distal part going to sinus venosus also degenerates. Its proximal part making sinusoids is left. This part connects placenta (oxygenated Blood) to liver. Proximal end→ sinus venosus end. Distal end→ placenta end. ➔Inferior mesenteric vein→ splenic vein. WHY UMBILICAL VEINS GO TO LIVER? Splenic vein + superior mesenteric vein→ hepatic portal vein→ breaks into 2 sinusoids derived from right and left vitelline veins. Because their function is to provide nutrients to baby just like portal vein of git. Actually, left sided Sinus Venosus regresses. Left hepatocardiac channel→ degenerate & its plexus connects to right hepatocardiac channel. So RHCC enlarges. 3.1.1 MAJOR DERIVATIVES OF VITELLINE VEIN • Portal vein draining superior mesenteric vein and splenic vein (draiing inf. Mesenteric) • Hepatic sinusoids • Right hepatocardiac channel→ enlarges→ hepatic portion of inferior vena cava. • Right hepatocardiac channel→ right hepatic vein • Left hepatocardiac channel→ left hepatic vein→ degenerate. ➔Blood from mother in umbilical vein already processed. So, it does not need much processing. Ductus venosus→ special channel connecting umbilical vein with Inferior vena cava. Most of blood→ ductus venosus Little blood→ sinusoids ➔A special type of sphincter in ductus venosus. During delivery→ uterus contracts→ puts pressure and squeezes placenta→ Lot of blood comes to Ductus venosus and heat may overload. ➔As soon as its ductus venosus stretches→ sphincter contracts→ blood diverted to sinusoids and slowly. So, heart may not overload. ➔After birth, we do not need umbilical vein. We cut it at naval point/ umbilicus. So, it will close→ no blood in this. Page 46 of 57 CARDIOVASCULAR SYSTEM DEV EMBRYOLOGY HASAN BAJWA N68 Page 47 of 57 CARDIOVASCULAR SYSTEM DEV Fibroblasts invade→ put collagen→ fibrotic cord→ connecting umbilicus to liver. This is called round ligament of liver or ligamentum teres. ➔Ductus venosus not needed also→ fibrotic→ ligamentum venosum 3.3 CARDINAL VEINS EMBRYOLOGY HASAN BAJWA N68 3.3.2 ANOMALY Sometimes there is left sided superior vena cava. This happens when right anterior cardinal vein disintegrates and left persists. Left part of sinus venosus remain intact. But it will drain into right atrium via coronary sinus. Blood draining from right to left. ➔Anterior and Posterior cardinal veins join near sinus venosus to form Common cardinal veins. ➔Left side of cardinal system degenerates. ➔right side overdevelops and contributes to rest of inferior vena cava. ➔Posterior cardinal system degenerates and new cardinal system develops for lower limbs. 3 new cardinal systems develop for posterior cardinal system. These are: 1. Supracardinal system. 2. Subcardinal system. 3. Sacrocardinal system. 3.3.1 ANTERIOR CARDINAL SYSTEM Anastomosis between anterior cardinal veins ➔For anterior cardinal system➔ channel develops→ moves blood from left to right side→ becomes wide→ superior vena cava. Superior vena cava develops from 1. Right anterior cardinal vein 2. Right common cardinal vein This anastomosis is called left brachiocephalic vein. 3.3.3 ANOMALY Sometimes both right and left anterior cardinal systems do not degenerate and there are two superior vena cavas. Right and left. No anastomosis needed. 3.3.4 POSTERIOR CARDINAL SYSTEM A part of IVC was developed from right vitelline vein. 3.3.4.1 Supracardinal system • Starts draining intercostal veins • Thoracic duct drains into this system • Right supracardinal vein→ connected to superior vena cava. (Azygous vein) • Right side→ 4 to 11th intercostals • Left side→ 4th, 5th, 6th, 7th intercostals • Anastomosis develops (Hemiazygous system). • Left supracardinal vein loses connection with left horn of sinus venosus because it degenerates. • So, left drains into right supracardinal vein. • From left supracardinal vein→ hemiazygous system. • From right→ Azygous system 3.3.4.2 Subcardnial system • Located on sides with kidneys • Taking blood from renal, suprarenal and gonads. Page 48 of 57 CARDIOVASCULAR SYSTEM DEV • • • • • EMBRYOLOGY HASAN BAJWA N68 A channel connects left with right (left renal vein shunting). Left side will degenerate. Right enlarges→ Inferior vena cava (RENAL PART) Left gonadal vein→ left renal vein Right gonadal vein→ Inferior vena cava directly. 3.3.4.3 Sacrocardinal system • Receive blood from lower limbs through right and left sacrocardinal system • Shunt develops from left sacrocardinal to right sacrocardinal system. This shunt→ part of left common iliac vein • Left degenerates. IVC develops from 3 sources 1. Hepatic part→ right vitelline vein 2. Renal part→ right subcardinal venous system 3. Post-renal part→ From right sacrocardinal system Throughout body, shunts are present. 1. Left brachiocephalic vein 2. Hemiazygous system 3. Azygous system Page 49 of 57 CARDIOVASCULAR SYSTEM DEV EMBRYOLOGY HASAN BAJWA N68 Page 50 of 57 CARDIOVASCULAR SYSTEM DEV EMBRYOLOGY HASAN BAJWA N68 Page 51 of 57