Fertilization and Implantation:

• Capacitation: a period of conditioning that occurs in the female reproductive tract, must happen in order for sperm to fertilize the ovum.
• Cortical Reaction: impermeability to other sperm
• Acrosome Rxn: fusion of the outer acrosomal mem. and sperm cell membrane
• Fertilization in ampulla of fallopian tube
• Day 3 = Morula enters the uterus…NOT the blastocyst
• Conceptus is termed a blastocyst
• Zona pellucida must degenerate (HATCHING) in order for implantation to occur
• Blastocyst usually implants in the endometrium by day 7 after fertilization
• Trophoblast differentiates to form inner cytotrophoblast and outer syncytiotrophoblast
• Decidual Rxn: occurs before the setting of the placenta at day 10 (progesterone control) to accumulate glycogen and lipids
• Embryoblast:  hypoblast (primitive embryonic endoderm) and epiblast
• Implantation is COMPLETE at day 10à complete interstitial implantation
• hCG can be detected in blood at day 8 and in urine at day 10
• Chorionic villi:  1^st (day 13), 2^nd (day 15), and 3^rd (day 18)
• Graft vs. Host Rxn: failure of implantation may involve immune rejection of the antigenic conceptus by the mother
• Bilaminar disc: epiblast and hypoblast

Placentation:

• Chorion:  trophoblast (both layers) and extraembryonic somatic mesoderm (epiblast) à fetal portion of placenta
• Maternal portion of the placenta is from the endometrium
• Epiblast -> extraembryonic somatic and visceral mesoderm
• Chorion frondosum: chorionic villi invaginating endometrial lining
• Chorion leave: it is avascular, smooth area
• functional layer of endometrium -> Decidual cells:  d. basalis (on the endometrial lining), d. capsularis (surrounding the conceptus), and d. parietalis (below d.c.)
• Placenta:  d. basalis, chorion frondosum, and intervillous space
• Amniotic sac enlarges FASTER than the chorionic sac
• Amniochorionic membrane à “water breaks”
• (Fetal) Placental septa -> cotyledons (consists of two or more villi and branches)
• DeO₂ leaves the fetus via 2 umbilical arteries; O₂ enters via the umbilical vein
• hCG: secreted by the syncytiotrophoblast…stimulates production of progesterone à beta is very specific
• NEITHER HYDATIDIFORM MOLE NOR CHORIOCARCINOMA CAN OCCUR WITHOUT PREGNANCY!!!!!
• HM: involves the conversion of the chorionic villi into a mass of vesicles that may fill the uterus
• Choriocarcinoma: cancer of chorionic epithelium
• Amnion & Amniotic Cavity…how does it form…fluid between bilaminar layer
• Yolk Sac becomes primitive gut and gives rise to epi. of trachea, bronchi, lungs
• Allantois & Blood vessels (will become umbilical vein and arteries)
• Umbilical Vein will become Ligamentum teres (left umbilical vein)
• Umbilical Arteries will become internal iliac artery and superior vesicle arteries

Early Development-Week 2 and 3 :

• Closing Plug: when the blastocyst continues to sink into the endometrial epithelium…a coagulation of blood…at day 10
• A primitive uteroplacental circulation is established at day 11-12…via lacunar network
• Chorionic villi:  increases the surface area for exchange of nutrients, gases, etc.
• Prechordal plate at day 13 will form from a portion of columnar hypoblast cells and epiblast cells…future site of the mouth
• Exocoelomic membrane (Heuser’s Membrane)…lining of primary yolk sac (exocoelomic cavity) by hypoblast cells that line inner surface of cytotrophoblast
• An acellular extraembryonic reticulum forms between the exocoelomic membrane and the cytotrophoblast
• Extraembryonic Somatic Mesoderm:  lines the inside of the cytotrophoblast
• E.Visceral M:  lines the outside of the cytotrophoblast
• Lacunae appears in the extraembryonic reticulum and will coalesce to form the extraembryonic coelom à will become the chorionic cavity
• Oncofetal genes: cell surface antigens that normally appear only on embryonic cells but can re-express themselves in human malignant cells
• Week of two’s Summary

a.      trophoblast differentiates into syncytiotrophoblast and cytotrophoblast

b.      embryoblast differentiates into epiblast and hypoblast

c.      extraembyronic mesoderm differentiates into E. somatic & E. visceral

d.      cavities formed are amniotic cavity and chorionic cavity

• Gastrulation -> trilaminar embryonic disc formation -> primitive streak, p. groove, p. node, p. pit, cloacal membrane, notochord, and 3 germ layers
• Primitive streak forms opposite to Prechordal plate
• Prechordal plate is the limit of elongation of the notochord
• Three layers where MESODERM is NOT found:  surrounding the notochord, cloacal membrane, and prechordal plate (2 layers only)
• Neuroenteric canal allows communication between the amniotic cavity and yolk sac for a day or two only
• Paraxial Mesoderm:  will form next to notochord and will divide into pairs of somtomeres -> somites (Sclerotome, myotome, and dermatome)…1-7 will not form somites but contribute to form pharyngeal arches…42-44 somites will be formed…somites form on day 20 (somites form at a rate of 3 per day)…occurs by the third week
• Intermediate Mesoderm:  forms urogenital ridge which will form kidney/gonads: gives rise to the lining of the organs
• Lateral Mesoderm:  intraembryonic coelom forms (I. Somatic and I. Visceral)
• LM à IM à PM à Notochord ß PM ß IM ßLM
• Ectoderm will form the future nervous system and epidermis
• Neurulation: Ectoderm ->  Neuroectoderm ->  Neural Plate ->  Neural Groove ->  Neural Folds fuse àNeural Tube…neural crest is formed above/forms spinal ganglion
• Intraembryonic coelem will become the peritoneal cavity
• Angiogenesis is the formation of blood vessels…Extraembryonic mesoderm differentiates into angioblasts à angiogenic cell clusters ->  endothelial cells (at periphery)
• Primitive blood 1^st forms (days 15-16) in the extraembryonic mesoderm assoc’d w/ the yolk sac, Later it forms the Allantois
• Intraembryonic mesoderm:  differentiate same way to give rise to blood vessels within the embryo (from lateral mesoderm)
• Hematopoesis is the formation of blood cells…it begins around the yolk sac and is taken to the organs…liver, spleen, thymus, and bone marrow
• Sacrococcygeal teratoma is a tumor that arises from the remnant of the primitive streak and occurs more commonly in female infants.
• Chordoma is a tumor that arises from the remnants of the notochord and occurs more commonly in men
• Allantoid cysts are remnants of the portion of the allontois.

Somites:

• HOX genes regulate…
  • development of the paraxial mesoderm, determines segmentation of the branchial apparatus, regulate patterning and shapes of vertebrae, determine the cranio-caudal position of limbs, regulate types and shapes of bones in the limb, craniosynostoses, syndactyly…it is affected by Vit A
• Remnant of notochord is observed as the nucleus pulposus (Intevertebral disk)…the vertebrae and ribs are formed by the sclerotome
• Sonic hedgehog (expressed in the notochord) changes the medial somite to sclerotome, organizes the digits
• Myotome splits into a dorsal epimere and a ventral hypomere; epaxial muscles are associated with the vertebral column (dorsal rami) and hypaxial muscles are associated with the body wall (ventral rami); dorsal (extensors) & ventral (flexors)
• Preotic myotomes forms the eye muscles;
• occipital somites form tongue muscles
• Head and neck muscles are formed from the branchial apparatus
• Limb muscles are from the lateral portions of the myotomes
• Epidermis gives rise to:
  •  
    •  nails,
    • hair shaft
    • tooth enamel,
    • sweat, mammary, and sebaceous glands (ectoderm)
• Dermis gives rise to:
  •  pulp and dentin (mesoderm)
• Brevicollis (Klippel-Feil Syndrome) is a fusion or shortening of the cervical vertebrae. (Short neck!)
• Spina bifida oculta:  occurs when scleratome move around the notochord
• Raschischisis:  severe (split spine)
• Amelia is the absence of limb; syndactyly has fused digits

Late Embryonic and Fetal Development:

• At 4^th week, the umbilical cord is the ONLY thing connecting the embryo to the mother.
• Embryonic folding occurs during this week
• Three concentric tubes:  the outer ectoderm, the mesodermal muscles and connective tissues of the body walls, and the inner endodermal gut tube
• Ectoderm ->  epidermis and derivatives/neuroectoderm;
• Mesoderm ->  Muscles (recall somite division);
• Endoderm ->  GI tract and respiratory system
• At the end of the 8^th week, ALL systems of the body are formed.
• At 8^th week, Embryo à Fetus
• The fetal period is characterized by rapid body and organ growth relative to the head growth (2^nd and 3^rd trimesters)
• Date of onset of last menstruation (most commonly used)…LNMP
• Fetuses born between weeks 22-28 have difficulty in surviving, mainly because of the immaturity of the lungs
• Between weeks 9-12…genitalia distinct, head is ½ size of fetus
• Between weeks 13-16…hematopoeisis in spleen
• Between weeks 17-20…uterus/testes form; fetal heartbeat can be heard with a stethoscope
• Between weeks 21-24…respiratory system begins surfactant production
• Between weeks 26-28…respiratory system matures
• Between weeks 29-32…pupillary reflex
• Between weeks 33-38…fetus orients to light and testes descend
• Not viable (less 500 g @ 22 weeks); Immature infants (500-1000g); Premature infants (1000-1500g)
• Amniocentesis:  performed after the 14^th week after LNMP
• Cordocentesis:  blood from umbilical arteries
• Alpha-fetoproteins:  high concentration is indicative of problems with the proper development of the nervous system
• 66% of twins are dizygotic; 34% are monozygotic
• Less than 1% are monochorial and monoamniotic
• Skin is the largest organ of the body
• Venix caseosa is sebum that covers the fetus
• Albinism is the absence of skin pigmentation (no melanin)
• Hemangiomas is blood and lymph vessels from dark stain
• Ichthyosis is excessive keratinization
• Psoriasis is the thickening of epidermis (excess cell proliferation)
• Ehlers-Danlos syndrome is a genetic defect in the production of collagen
• Alopecia is the absence of hair
• Hypertrichosis is excessive hairiness
• Pili torti is twisted hair
• Hairs begin to develop in the 2^nd month, but are not visible until week 20
• Gynecomastia is excessive male mammary glands
• Polymastia is an excessive number of breasts
• Polythelia is an excessive number of nipples
• Amelogenesis imperfecta is defective enamel
• Dentinogenesis imperfecta is defective dentin
• Discoloration of teeth is the discoloration due to substance incorporated in dentin
• Denta Perfecta is Michelle Doguet

Body Cavity & Respiratory System:

• Recall, at week 4, embryonic folding begins
• Curved portion will form the future pericardial cavity (ventrally/caudally)…it is initially located in front of the neural tube and oropharyngeal membrane
• Arms become the pericardioperitoneal canals and peritoneal cavity (from intraembryonic coelom)
• Yolk sac becomes the primitive gut
• Ventral mesenteries degenerate to form a single peritoneal cavity
• Thoracic cavity formation…pleuropericardial folds will become a membrane, lungs are getting bigger and fill space forming the pleural cavities and mediastinum…pleuropericardial folds will separate from intraembryonic coelom from two lateral spaces which will give rise to the fibrous pericardium…
• Pericardioperitoneal folds/membrane will separate the pericardial cavity from the pleural portion from what will later become the pleuroperitoneal cavities
• The anterior portion of the diaphragm is formed by the sandwiching of the SEPTUM TRANSVERSUM between the heart and yolk sac (peritoneal cavity)…then, septum transversum will fuse with pleuroperitoneal folds to form the lateral-posterior regions of the diaphragm…the central part of the diaphragm is the fusion of the pericardioperitoneal canals with the dorsal mesentery of the esophagus…the edges are formed by muscular ingrowth from the body wall
• Diaphragm is innervated by C3, C4, and C5…forming the phrenic nerve…is both motor and sensory to the diaphragm…sensory from the body wall (intercostal) nerves
• Congenital diaphragmatic hernia:  a posterolateral defect (most often on the left) due to faulty closure to the pleuroperitoneal membrane…foramen of Bochdalek
• Respiratory system forms from the floor of the 4^th pharyngeal pouch called the laryngotracheal groove
• Laryngotracheal groove à L. Diverticulum à L. Tube
• Tracheoesophageal folds à T. Septum à separates into anterior L. tube and a posterior esophagus
• Neural crest cells from branchial arches 4 and 6 will give rise to laryngeal cartilages and muscles
• Tracheoesophageal fistula is the faulty formation and separation of the tube from the esophagus
• Lung development:  a lung bud à bronchial bud à lobar bronchi à segmental bronchi à bronchioles à alveoli
• Four periods of lung development: 
  • 1. Pseudoglandular à no gas exchange elements are present and a fetus born at this stage will not survive…
  • 2. canalicular à respiratory bronchioles, alveolar ducts and primitive alveoli are present…lung is well vascularized…may survive with ICU…
  • 3. Terminal sac à Type I used for respiration and Type II for surfactant production…
  • 4.  Alveolar à respiratory membrane matures and surfactant production increases just before birth
• 95% of alveoli are produced after birth
• Surfactant production begins at about week 20, but the greatest amounts are produced two weeks right before birth…inadequate production of it could lead to RDS (lead to immediate asphyxiation and permanent damage to Type II cells) and HMD – hyaline membrane disease (characterized by collapsed alveoli ->

Cardiovascular I and II:

• The cardiovascular system is the first major system to function in order to sustain the rapidly growing embryo
• Appears 18 day (mid-week 3) before embryonic folding
• Angioblastic cords à 2 endocardial heart tubes à fuse into 1 endocardial tube
• Heartbeats can be heard about week 4
• Cardiac jelly is a gel that separates the endocardium and myocardium
• Epicardium is the serous visceral pericardium (from mesothelium)
• S. A. V. B. T. A.….sinus venosus, atrium, ventricle, bulbus cordis, truncus arteriosus, aortic arch and arches…first asymmetrical developmental change (cardiac looping)
• V.B.T.A. moves anterior and SA loops posterior-dextral looping
• Mesocardium (a mesentery-like structure) will become the transverse pericardial sinus in the adult
• Endocardial cushions fuse to form the left and right atrioventricular canals
• Septum primum will close the foramen primum and will degenerate superiorly forming the foramen secundum
• The septum secundum develops on the right atrium to the right of the septum primum
• Septum secundum closes the foramen secundum
• Foramen ovale will become the fossa ovalis…it is closed by the septum primum
• High right atrial pressure allows displacement of septum primum towards the left atrium…forming a R -> L shunt
• Embyonic atria are seen in the adult as auricular appendages
• Right sinus venosus will become the sinus venarum (externally is the sulcus terminalis and internally as the crista terminalis)
• Left sinus venosus becomes the coronary sinus
• Primitive IV septum fuses with endocardial cushions (muscular region of IV)
• Aorticopulmonary septum will become an anterior pulmonary trunk and a posterior ascending aorta
• Aorticopulmonary septum fuses with IV septum to complete the portioning of the ventricles
• Bulbus cordis -> conus arteriosus (infundibulum) of the right ventricle, aortic vestibule of the left ventricle
• Six aortic arches: 
  • 1^st gives rise to portions of the maxillary and external carotid arteries…
  • 2^nd gives to the stapedial artery…
  • 3^rd gives rise to the common carotid and portions of the internal carotid…
  • 4^th is the aortic arch on the left and the subclavian artery on the right…
  • 5^th nothing…
  • 6^th gives rise to the right and left pulmonary arteries and left ductus arteriosus
• Vitelline veins will give rise to the portal system veins, hepatic sinusoids and hepatic veins, part of IVC, and ductus venosus
• LEFT Umbilical vein will give rise to Ligamentum teres…right degenerates
• Cardinal veins constitute main venous drainage of the embryo
• Anterior and posterior come together as the common cardinal
• Anterior cardinal veins give rise to the SVC, jugular, and brachiocephalic veins
• Posterior cardinal veins will become subcardinal and then supracardinal…will give rise to the IVC, azygous, common iliac, renal, gonodal, hemiazygous, and intercostal veins
• Six primary lymphatic sacs by week 8…jugular, iliac, retroperitoneal, cysterna c.
• Cysterna chyli is the first part of the thoracic duct
• Thoracic duct = cysterna chyli and jugular sacs
• Thoracic duct shifts from right to left at the sternal angle or T4/5
• 1^st bypass…ductus venosus…1^st shunt (foramen ovale)…2^nd (ductus arteriosus)
• Valve of the IVC directs O2 blood thru foramen ovale

Congenital Heart Defects:

• Looping, Remodeling of the Great Vessels, Septation, and Outflow Tract
• Looping
  • D-Looping is “normal” looping
  • Dextrocardia with situs inversus (it is ok)…without situs inversus (you are S.O.L)…and dextrocardia is the most frequent positional abnormality
• Remodeling of the Great Vessels
  • Patent Ductus Arteriosus: occurs when the ductus arteriosus, a connection between the pulmonary artery and aorta, fails to close…L à R shunt…can be treated with prostaglandin synthesis inhibitors (ie. Indomethacin)…abnormal closure results in a postductal coarctation…surviving Turner syndrome patients have this type of coarctation…Functional closure (1-2 hrs after birth) and anatomical closure (1-2 weeks)…abnormality of 6^th aortic arch…very common in premature infants, hypoxia, and maternal rubella infection
  • Preductal Coarctation of the Aorta occurs before (superior) the ductus arteriosus
  • Postductal Coarctation of the Aorta occurs after (inferior) the ductus arteriosus…commonly associated with Turner Syndrome…99% of TS fetuses have this type of malformation
• Septation
  • Atrial Septal Defects (ASD)
    • Foramen Primum defect is caused by a failure of the endocardial cushion to fuse with septum primum…results in a condition in which the foramen primum is never closed…generally accompanied by an abnormal MITRAL valve
    • Foramen Secundum defect results in a condition in which there is an opening between the right and left atria…normally higher in the atrial wall…most common in females…most common clinically significant ASD
    • Probe patency of the foramen ovale is caused by incomplete fusion of septum primum and septum secundum
    • Persistent common AV canal defect is caused by failure of fusion of the dorsal and ventral AV cushions…L à R shunt…associated with mitral valve regurgitation
  • Ventral Septal Defects (VSD)-most common heart malformation
    • Membranous VSD is the most common…is caused by faulty fusion of the right bulbar ridge, left bulbar ridge, and AV cushions…results in a condition in which an opening between the right and left ventricles allows free flow of blood…L à R shunt
    • Muscular VSD are rare
• Outflow Tract
  • Persistent Truncus Arteriosus is caused by abnormal neural crest cell migration such that there is only PARTIAL development of the AP septum…DiGeorge Syndrome is defective NCM…chromosomal microdeletion 22q11…cyanosis
  • D-Transposition of the great arteries is caused by abnormal NCM such that there is NON-SPIRAL development of the AP septum…cyanosis
  • Tetralogy of Fallot is a problem with the heart and blood vessels…it is primarily depends on the severity of the pulmonary stenosis…4 classic malformations…
    • pulmonary stenosis,
    • overriding aorta,
    • membranous VSD,
    • right ventricular hypertrophy
  • Cyanosis is a R -> L shunting, “blue”, most common cause of cyanosis is ToF, 8% of CHD, associated with Down’s Syndrome (Trisomy 21)

Tags: acrosome reaction, allantoid cysts, amelia, angiogenesis, bilaminar disk, capacitation, choriocarcinoma, chorion frondosum, chorionic villi, coceptus, cortical reaction, decidual reaction, dorsal epimere, embryoblast, epiblast, exocoelomic membrane, extreembryonic mesoderm, hcg, hematopoesis, heuser's membrane, HOX genes, implantation, intraembryonic mesoderm, morula, myotome, neurulation, occipital somites, oncofetal genes, pericardioperitoneal folds, placenta, placentation, prechordal plate, preotic somites, raschischisis, sacrococcygeal teratoma, sonic hedgehog, spina bifida, trophoblast, venix caseosa, ventral hypomere, zona pellucida

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