Developmental Anatomy Lecture Syllabus Department of Histology & Embryology Peking Union Medical Collage 2007.12 Content 1. INTRODUCTION TO THE DEVELOPING HUMAN ..................1 2. EARLY DEVELOPMENT OF HUMAN EMBRYO.......................2 3. HUMAN BIRTH DEFECTS............................................................ 11 4. DEVELOPMENT OF HEAD AND NECK ....................................14 5. DEVELOPMENT OF BODY CAVITIES AND DIAPHRAGM ..17 6. DEVELOPMENT OF RESPIRATORY SYSTEMS .....................19 7. DEVELOPMENT OF DIGESTIVE SYSTEMS............................21 8. DEVELOPMENT OF URIGENITAL SYSTEM ...........................25 9. DEVELOPMENT OF CARDIOVASCULAR SYSTEM ..............30 10. DEVELOPMENT OF THE NERVOUS SYSTEM .......................34 1 INTRODUCTION TO THE DEVELOPING HUMAN I. Definition: 1. Embryology: developmental anatomy, the study of the formation and development of embryos. 2. Human embryology is a science that studies the normal development as well as the birth defects of a human being in the maternal uterus. II. The History of Embryology 1. Early History 2. Renaissance History 3. Experimental Embryology 4. Progress of modern embryology: test tube babies & somatic cell cloned animals III. The main branches of Embryology 1. Descriptive Embryology 2. Comparative Embryology 3. Experimental Embryology 4. Chemical Embryology 5. Molecular Embryology 6. Reproductive Engineering 7. Teratology IV. Why a medical student should study Embryology? V. Introduction of the development of an embryo prenatal periods fertilization parturition 38 weeks fertilization age & gestational age Three developmental periods are divided: 1. Preembryonic period (0-2 weeks): fertilization to formation of the bilaminar germ disc. 2. Embryonic period (3-8 weeks): trilaminar embryonic disc formation & organogenesis 3. Fetal period (9-38 weeks): growth of the organ systems. 1 EARLY DEVELOPMENT OF HUMAN EMBRYO I. Gametogenesis A process of formation and maturation of the gamete (spermatozoa in male and ova in female), including chromosomal and morphological changes. 1. Migration of primordal germ cells (PGCs) 2. Spermatogenesis 3. Oogenesis II. Fertilization to Implantation (1st Week of Development) 1. Fertilization: A sperm + an oocyte → zygote 1) before fertilization (1) male gametes (spermatozoa) a. number and viability: b. transport of ejaculated spermatozoa capacitation of spermatozoa: site: in the female genital tract method: removal of a glycoprotein coat from the plasma membrane of the acrosomal region result: obtaining capacity of fertilizing an egg (2) female gamete (oocyte) a. number b. transport of ovulated secondary oocyte (3) two gametes meeting a. time: spermatozoa: < 48 hours after ejaculation oocyte: 12 - 24 hours after ovulation b. site: ampulla of oviduct 2) process of fertilization (1) acrosome reaction: release of enzymes from acrosome (2) zona reaction: zona becomes impenetrable to other sperm (monospermy), through lysosomal enzyme release from cortical granules of oocyte to change structure and composition of the zona. (3) process of fertilization: penetration, recognition & fusion ZP3 is responsible for species-specific fertilization 3) after fertilization (1) oocyte finishes 2nd meiosis (2) formation and merge of male and female pronuclei → cleavage 2 4) Result of fertilization (1) restoration of diploid number of chromosome (2) species variation (3) primary sex determination: Y+X = male, X+X = female (4) activation of egg metabolism and initiation of cleavage 2. Cleavage and blastocyst formation mitotic division zygote blastomeres → morula → blastocyst compaction (embryoblast) inner cell mass blastocyst blastocyst cavity trophoblast embryonic stem cell (ES cell) hatching of blastocyst: ~ day 5- 6 3. Implantation: a process of the blastocyst embedding into the endometrium 1) Time: Day 5 - 6 to Day 11 - 12 2) Site: posterior or anterior wall of uterine body 3) Process: adhesion, expansion, dissolution, invasion, differentiation, repair 4) The main changes during implantation (differentiation) (1) Formation of bilaminar embryonic disc (embryoblast) epiblast inner cell mass → embryonic disc hypoblast (2) Decidual reaction decidua basalis Decidua decidua capsularis → degeneration decidua parietalis (3) Formation of the early fetal membranes cytotrophoblast trophoblast ↓ syncytiotrophoblast 3 epiblast hypoblast ↓ exocoelomic membrane (& cavity) amnioblasts amnion extraembryonic endoderm of primary yolk sac primitive streak late early extraembryonic mesoderm secondary yolk sac allantois extraembryonic somatic connecting stalk mesoderm extraembryonic coelom cytotrophoblast syncytiotrophoblast chorion extraembryonic mesoderm umbilical cord chorionic cavity chorionic sac 5) Requirements of implantation (1) Zona pellucida disappears in time (2) Normal development and transport of the young embryo (3) Endometrium in secretory phase (4) Normal endocrine regulation 6) Abnormal implantation (1) Ectopic pregnancy (2) Placenta previa 7) Contraception (1) Intervening the processes of gamete production: contraceptive pills (2) Intervening the processes of fertilization a. condom & diaphragm b. terilization: vasectomy & tubal ligation (3) Intervening the processes of implantation a. intrauterine devices (IUD) 4 splanchnic b. post-coital contraception 4. Human assistant reproductive technology 1) Artificial insemination 2) In vitro fertilization-embryo transfer, IVF-ET 2nd week -- “ the period of twos” two embryonic layer: epiblast & hypoblast two trophblast layers: cytotrophoblast & syncytiotrophoblast two cavities: amniotic cavity & yolk sac III. Formation of three germ layers (3rd Week) 1. Gastrulation: Gastrula epiblastic cells proliferation & migration bilaminar embryonic disc trilaminar embryonic disc 1) Formation of the primitive streak primitive streak & primitive groove epiblastic cells → primitive knot & primitive pit 2) Formation of intraembryonic endoderm and mesoderm 3) Formation of trilaminar germ disc All 3 germ layers are derived from the epiblast. There are two areas that have no mesoderm: prechordal plate → oropharyngeal membrane cloacal membrane 4) Formation of the notochord (1) Process: primitive node & primitive pit (median cranial migration) → notochordal (head) process → notochordal canal (neurenteric canal) → notochordal plate → notochord (2) Function: primary inductor, induction of neural plate formation 5) Fate of the notochord & primitive streak (1) The fate of notochord: degeneration, forming the nucleus pulposus of intervertebral disc (2) The fate of primitive streak: degeneration (3) Teratoma: oropharyngeal & sacrococcygeal teratoma 2. Neurulation: the process of neural tube formation Neurula 1) Formation of the neural tube proliferation invagination ectoderm cells (overnotochord) neural plate neural groove & neural fold → neural tube The neural tube is the primordium of the central nervous system (CNS). 2) Formation of the neural crest The neural crest is the primordium of the peripheral nervous system (PNS). 5 3rd week -- “period of threes” three germ layers: ectoderm, mesoderm & endoderm three important structure: primitive streak, notochord & neural tube IV. Differentiation of Germ Layers and Establishment of Body Form (3 rd to 8th Week) 1. Differentiation of ectoderm 1) Neural ectoderm (1) neural tube → CNS rostral (anterior) neuropore: closed by 25-26 days caudal (posterior) neuropore: closed by 27-28 days (2) neural crest → PNS, the chromaffin cells of the adrenal medulla, parafollicular cells of the thyroid, melanocytes, and part of mesenchyme in the pharyngeal apparatus. (3) anencephaly & myeloschisis (spina bifida) 2) Surface ectoderm (1) epidermis and its appendages (2) adenohypophysis (3) sensory epithelium of the ear, nose, tongue (4) lens of the eye (5) enamel of the teeth 2. Differentiation of mesoderm paraxial mesoderm → somites mesoderm → intermediate mesoderm lateral mesoderm 1) Derivatives of the somite somites ( 3 pairs/day, 42 - 44 pairs in total ) sclerotome → paraxial skeleton somite → myotome → muscles dermatome → dermis 2) Derivatives of the intermediate mesoderm the primordium of the urogenital system forming the kidneys and gonads, etc. 3) Derivatives of the lateral mesoderm somatic mesoderm → bones, muscles and C.T. and mesothelium lateral lining inner surface of body wall mesoderm→ intraembryonic coelom splanchnic mesoderm → muscles and C.T. of viscera, and mesothelium covering them 6 3. Folding of the embryo the embryonic disc rapid growth of somites Folding rapid growth of CNS ↓ head and tail folds lateral fold cylindrical embryo 4. Formation of primitive gut york sac → primitive gut (foregut, midgut, hindgut) → primordium of digestive and respiratory systems 5. Differentiation of endoderm endoderm → epithelial of digestive & respiratory tract, and bladder, urethra; parenchyma of liver, pancreas, tonsil, thyroid, parathyroids, thymus; epithelium of tympanic cavity and Eustachian tube. V. Fetal membranes and placenta fetal membranes including chorion, amnion, yolk sac, umbilical cord & allantois Functions: nutrition, protection, respiration, excretion, endocrine & immunological barrier preventing rejection of fetus as an allograft 1. Chorion extraembryonic somatic mesoderm + cytotrophobalst + syncytiotrophoblast 1) Chorionic villi (1) development of villi: primary stem villi: cytotrophoblast + syncytiotrophoblast ↓ secondary stem villi: with a core of loose C.T. ↓ tertiary stem villi: with blood vessels in the loose C.T. core (2) cytotrophoblastic shell (细胞滋养层壳) stem villi (anchoring villi) , branch villi (terminal villi) (3) villous chorion (丛密绒毛膜 chorion frondosum) & smooth chorion (平滑绒 毛膜 chorion leave) 2) intervillous space isolated lacunae in the syncytiotrophoblast → fused to lacunar networks → intervillous space chorionic plate, primitive uteroplacental circulation 3) abnormal growth of the trophoblast: Hydatidiform Moles (葡萄胎), Choriocarcinomas (绒毛膜癌) 2. Amnion & Amniotic fluid 1) amniotic sac, amniotic cavity & amniochorionic membrane 2) amniotic fluid 7 (1) origin: amniotic cells, maternal & fetal blood, tissue fluid and fetal urine etc. (2) circulation and exchange: a. by mother b. by fetus (3) composition: (4) volume: 10w: 30ml, 20w: 350ml, 37w: 700-1000ml < 400ml → oligohydramnios > 2000ml → polyhydramnios amnionic band (5) significance: a. protection b. prevent adherence of the amnion to the embryo and fetus c. controlling the embryos temperature d. enabling the embryo to move freely and grow e. maintaining homeostasis of fluid and electrolytes f. permitting normal fetal lung development g. dilating and washing the cervix during the labor h. prenatal diagnosis Amniocentesis -Fetoprotein (-AFP) premature rupture of the amnion 3. Yolk sac 1) significance: (1) transfer of nutrients (2-3w) (2) blood development (mesoderm, 3-5w) (3) primitive gut (4w) (4) primordial germ cells (endoderm, 3w) 2) fate: yolk stalk → Meckels diverticulum(憩室) 4. Allantois 1) origin: finger-like diverticulum from the caudal wall of the yolk sac that extends into the connecting stalk 2) significance: (1) blood formation: 3-5w (2) umbilical vein and arteries (3) a part of urinary bladder 3) fate: urachus (脐尿管) → median umbilical ligament 5. Umbilical cord mucous connective tissue covered by amnion, including two arteries, one vein, atrestic allantois and atrestic yolk stalk 1-2cm in diameter, 30-90cm in length (average 55cm) false knots and true knots 8 6. Placenta 1) Composes and Shape: (1) composes: fetomaternal organ the fetal component: the villous chorion the maternal component: the decidua basalis (2) shape: discoid, 15-20cm in the diameter, 2-3cm thickness, 500-600gm weight a. maternal surface of the placenta: rough cotyledon(胎盘小叶), groove (placenta septa) b. fetal surface of the placenta: smooth amnion, umbilical cord, and radiating chorionic vessels 2) The fetomaternal junction cytotrophoblastic shell, stem villi (anchoring villi) placenta accrete (植入胎盘), placenta increta, placenta percreta (穿透性胎盘) 3) Placental circulation fetal placental circulation ( within the villus ) umbilical A. →→ arterio-capillary-venous system →→ umbilical V. metabolic gaseous products products spiral A. → intervillous space → endometrial V. maternal placental circulation intrauterine growth retardation (IUGR) 4) Placental membrane or Placental barrier (1) < 20w a. syncytiotrophoblast b. cytotrophoblast and basal lamina c. connective tissue in the chorionic villi e. endothelium and basal lamina of the fetal capillary (2) > 20w a. syncytiotrophoblast and basal lamina b. endothelium and basal lamina 5) Functions of placenta (1) metabolism (2) transport of substances nutrients, gases, waste products, drugs, hormones, Ag, Ab, etc (3) endocrine secretion a. protein hormones: human chorionic gonadotropin (hCG) human chorionic somatomammotropin (hCS) or human placental lactogen (hPL) human chorionic thyrotropin (hCT) human chorionic corticotropin (hCACTH) 9 b. steriod hormones: progesterone estrogens VI. Parturition (分娩) VII. Twins and other multiple pregnancies 1. Twins 1) dizygotic twins (双卵双胎) same or different sex the external and genetic features are no more alike than other brothers or sisters. separate placenta, chorionic sac and amniotic cavity sometimes two placentas fuse into one 2) monozygotic twins (单卵双胎) same sex, very similar physical appearance identical blood groups and genetic makeup (1) separation of the embryonic blastomere (35%) separate placenta, chorionic sac and amniotic cavity sometimes two placentas fuse into one (2) separation of the inner cell mass (65%) common placenta and chorionic sac separate amniotic cavity sometimes having placental vascular anastomoses Twin transfusion syndrome (3) division of the embryonic disc a. separate twins b. conjoined Twins (联胎) c. parasitic twin (寄生胎) 2. Other multiple pregnancies 1) Triplets 2) Quadruplets 10 HUMAN BIRTH DEFECTS I. Introduction 1. What’s birth defect? Developmental disorders present at birth (congenital malformations) Structural, functional, metabolic, behavioral or hereditary 2. Teratology 3. Incidence of birth defect Leading cause of infant mortality Major anomalies 2-3%; Minor anomalies 15% II. Causes of birth defects 1. Genetic factors 1) Numerical abnormalities of chromosomes (1) Autosomes a. Trisomy 21 (Down’s syndrome) Incidents -- maternal age < 25yrs: 1/2000; maternal age > 40yrs: 1/100 With heart defect and simian crease Mosiacism b. Trisomy 18 (Edwards syndrome) c. Trisomy 13 (Patau syndrome) (2) Sex chromosomes a. Turner’s syndrome (XO): Short stature, webbed neck, lymphedema, no ovary, mental retardation b. Klinefelter’s syndrome (XXY) Testicular atrophy, sterility, gynecomastia c. Tetrasomy and pentasomy (3) Triploidy and Teraploidy 2) Structural abnormalities of chromosomes (break, deletion, insertion, etc.) (1) Cri du chat syndrome Loss or misplacement of genetic material from chromosome 5 (2) Prader-Willi syndrome and Angelman syndrome Deletion of q11-13 on parental ch15 3) Mutations of genes: a few malformations (1) Phenylketonuria (PKU) (2) Achondroplasia (3) Fragile X syndrome 2. Environmental factors (teratogens) A teratogen is any agent that can produce a congenital anomaly or raise the incidence of an anomaly in the population. • The embryonic period (weeks 3-8) is highest susceptible because of intensive 11 differentiation. • Different organs have different susceptible period corresponding to their own critical development stage • Different teratogens also have different susceptible period. 1) Drugs (1) Social drugs a. Cigarette: nicotine causes hypoxia intrauterine growth retardation (IUGR) b. Alcohol: fetal alcohol syndrome (FAS): Flat midface, indistinct philtrum, thin upper lip, mental retardation, etc (2) Oral contraceptive and diethylstilbestrol (DES): Vertebral, Anal, Cardiac, Trachea, Esophageal, Renal, Limb (3) Antibiotics a. Tetracycline: bones and teeth defects b. Streptomycin derivatives: deafness (4) Anticoagulants: warfarin, 6-12w: hypoplasia of the nasal cartilage, stippled epiphyses, CNS defects Later: mental retardation, optic atrophy, microcephaly (5) Anticonvulsants a. Trimethadione: fetal trimetadione syndrome b. Phenytoin: Fetal hydantoin syndrome (6) Antineoplastic agents aminopterin (Folic acid antagonist): CNS & skeletal defect (7) Isotretinoin (8) Thalidomide (24-36d) meromelia, ear & heart defects, hemangioma, urinary & alimentary anomalies 2) Environmental chemicals (1) Methylmercury: Minamata disease (水俣病)→ brain damage (2) Lead: IUGR, fuctional deficits (3) Polychlorinated biphenyls (PCBs): IUGR, skin discoloration 3) Infectious agents (1) Rubella (4-5w) Congenital rubella syndrome (CRS): cataract, cardiac defects, deafness (2) Cytomegalovirus (CMV) Early: spontaneous abortion Later: IUGR, eye defects, microcephaly, cerebral palsy, hepatosplenomegaly (3) Herpes simplex virus (HSV) (4) Varicella (5) Human immunodeficiency virus (HIV) (6) Toxoplasmosis Early: fetal death Later: mental deficiency, microcephaly, microphthalmia, hydrocephaly (7) Congenital syphilis 12 4) Radiation (1) Atomic bomb: CNS malformations (2) Electromagnetic fields (3) Ultrasonic waves 5) Maternal factors (1) Diabetes mellitus (2) PKU 6) Mechanical factors (1) Oligohydramnios (2) Amniotic bands Congenital dislocation of the hip and clubfoot 3. Multifactorial inheritance III. Diagnosis and treatment 1. Education 1) Away from deleterious factors 2) Folate supplementation 2. Prenatal Diagnosis 1) Maternal serum screening: CMV, AFP…. 2) Ultrasound 3) Amniocentesis 4) Chorionic villus sampling 3. Treatment 13 DEVELOPMENT OF HEAD AND NECK I. Origin and development of the pharyngeal (branchial) apparatus 1. Origin of the Pharyngeal Apparatus---from neural crest Appear in 4-5th week, disappear by the end of 6th week The pharyngeal apparatus include: 1) Pharyngeal arches 2) Pharyngeal grooves (clefts) 3) Pharyngeal membranes 4) Pharyngeal pouches 2. Development of the Pharyngeal Apparatus 1) Fate of pharyngeal arches (1) 1st arch mandibular process (prominence) Face maxillary process (prominence) (2) 2nd arch (hyoid arch) Neck a. Derivatives of the pharyngeal arch cartilages b. Derivatives of the pharyngeal arch muscles 1st arch → mastication, 2nd arch → facial expression c. The cranial nerves supplying the pharyngeal arches 2) Fate of pharyngeal grooves (1) 1st groove the external auditory meatus (2) 2nd, 3rd, 4th groove cervical sinus degeneration Congenital anomalies: a. Branchial cysts & sinuses failure of closure of cervical sinus (cyst); may connect to surface or pharynx (sinus); along anterior border of sternocleidomastoid muscle b. Branchial fistulas 3) Fate of pharyngeal membranes (1) 1st membrane tympanic membrane (2) 2nd, 3rd, 4th membrane degeneration 4) Fate of pharyngeal pouches (1) 1st pouch → tubotympanic recess distal portion →primitive tympanic cavity proximal portion → auditory tube (2) 2nd pouch → palatine tonsil (3) 3rd pouch dorsal portion inferior parathyroid gland ventral portion thymus (4) 4th pouch dorsal portion superior parathyroid gland ventral portion ultimobranchial body (5) 5th pouch → ultimobranchial body parafollicular cells Congenital anomalies: Ectopic parathyroid gland 14 II. Development of the face (4-8W) 1. Primordia 5 prominences around stomodeum Single frontonasal prominence Paired maxillaryprominences Paired mandibular prominences 2. Development 1) Mandibular prominences lower jaw and lip 2) Maxillary prominence cheek and lateral upper lip 3) Frontonasal prominence upper part → forehead medial nasal prominence lower part → nasal placode nasal pits → nasal cavity lateral nasal prominence medial nasal prominences nasal septum & apex philtrum fuse maxillary prominence fuse lateral nasal prominence → alae, lateral wall of nose nasolacrimal groove → nasolacrimal duct 4) Stomodeum → oral cavity Nasal sac → nasal cavity III. Development of the palate (5-12W) medial nasal prominences → nasal septum maxillary prominence intermaxillary segment 1 median palatine process (primary palate) (anterior to the incisive fossa) 2 lateral palatine processes (secondary palate) (posterior to the incisive fossa) fuse palate Congenital anomalies: Facial clefts (clefts lip and (or) palate) 1. Cleft lip: division of upper lip, unilateral or bilateral Failure of maxillary prominence to fuse with medial nasal prominence 2. Oblique facial cleft: division extending from the upper lip to medial margin of orbit Failure of maxillary prominence to fuse with lateral nasal prominence 15 3. Cleft palate: uni- or bilateral, complete or incomplete, with or without cleft lip Failure of lateral palatine process to fuse with each other or with median palatine process IV. Development of the tongue (~ 4W) 2 distal tongue bud(lateral lingual swelling) median sulcus 1st arch overgrowing oral part (anterior to foramen cecum) 1 median tongue bud (tuberculum impar) 2nd arch copula overgrowing pharyngeal par (posterior to foramen cecum) 3rd & 4th arch hypobranchial eminence Congenital anomalies: Ankyloglossia (tongue-tie) and macroglossia V. Development of the thyroid gland (24d-7w) Foramen cecum median endodemal thickening Thyroid diverticulum thyroglossal duct Thyroid gland Congenital anomalies: 1. Thyroglossal duct cysts and sinuses: median location 2. Ectopic thyroid gland 16 DEVELOPMENT OF BODY CAVITIES AND DIAPHRAGM I. Early Development of the Intraembryonic Coelom 1. coelomic spaces 3w end, small, isolated coelomic spaces in the lateral mesoderm & cardiogenic mesoderm 2. horseshoe-shaped intraembryonic coelom 4w beginning, horseshoe-shaped intraembryonic coelom, communicated with extraembryonic coelom somatic mesoderm lateral mesoderm splanchnic mesoderm 3. partitioning of the intraembryonic coelom 4w, embryonic folding pericardial cavity intraembryonic coelom pericardioperitoneal canals(心包腔腹膜腔间管,胸膜管) peritoneal cavity 10w, peritoneal cavity separated from extraembryonic coelom II. Partitioning of the Coelom due to growth of the bronchial buds 1. the pleuropericardial membranes (心胸隔膜) 1) 5w, the cranial ridges:the pleuropericardial fold → the pleuropericardial membranes (contain the common cardinal vein) 2) 7w, fuse with mesoderm ventral to the esophagus the right opening closed earlier than the left one 3) primordial pleural cavity expand ventrally thoracic wall body wall fibrous pericardium(心包纤维层) 2. the pleuroperitoneal membranes(胸腹隔膜) 1) 5w, the caudal ridges: the pleuroperitoneal folds → the pleuroperitoneal membranes 2) 6w end, fuse with the septum transversum & the dorsal mesentery of esophagus right opening closed earlier than the left III. Development of the Diaphragm 1. components 17 primordial diaphragm septum transversum → the central tendon pleuroperitoneal membranes → small portion dorsal mesentery of esophagus → the crura lateral body walls (9-12w) → peripheral portion diaphragm 2. position changes and innervation of the diaphragm 4 w 3-5 cervical somites (5w, myoblasts migration, phrenic nerves) 6w thoracic somites 8w first lumbar vertebra IV. Congenital Anomalies 1. congenital diaphragmatic hernia (CDH) defective formation &/or fusion of the pleuroperitoneal membrane with other parts 2. eventration of the diaphragm (膈膨升) failure of muscular tissue extend into the pleuroperitoneal membrane 18 DEVELOPMENT OF RESPIRATORY SYSTEMS(R.S.) I. Development of the Trachea, Bronchi and Lungs 1. respiratory primordium 4w laryngotracheal groove ↓ 4w end laryngotracheal diverticulum tracheoesophageal → folds tracheoesophageal septum esophagus laryngotracheal tube trachea (primordium of the lower R.S. ) lung bud 2. histology endoderm: epithelium and glands splanchnic mesoderm: CT, cartilage, smooth muscle, etc. 3. development of the trachea 4. development of the bronchi and lungs lung bud (4w end) → bronchial buds → main bronchus (5w) → secondary bronchi → segmental bronchi (7w) → 17 orders of branches, respiratory bronchioles developed(24w) → additional 7 orders (after birth) II. Maturation of the Lungs 1. the pseudoglandular period (5-17 w) (假腺期) the bronchi and terminal bronchioles formed columnar epithelium 2. the canalicular period (16-25 w) (小管期) lumina of bronchi & bronchioles enlarged respiratory bronchioles (24w) developed terminal sacs (primordial alveoli) appeared lung tissue highly vascularized 3. the terminal sac period (24 w - birth) (终末囊泡期) terminal sacs developed epithelium: cuboidal → squamous type I alveolar cells type II alveolar cell: pulmonary surfactant alveolocapillary membrane(肺毛细血管膜)established 19 4. the alveolar period (late fetal period – childhood) (肺泡期) respiratory bronchioles & primitive alveoli increase primordial alveoli → mature alveoli • lung fluid III. Congenital Anomalies 1. tracheoesophageal fistula defective tracheoesophageal septum 2. respiratory distress syndrome (RDS, hyaline membrane disease) surfactant deficiency 3. lung hypoplasia oligohydramnios, CDH, etc. 20 DEVELOPMENT OF DIGESTIVE SYSTEMS I. Primitive Gut Tube 1. formation 4w, embryonic folding dorsal part of the yolk sac + splanchnic mesoderm → primordial gut 2. histology endoderm → most of the epithelium & glands splanchnic mesenchyme → CT, muscular, & other layers ectoderm of stomodeum & proctodeum oropharyngeal membrane, cloacal membrane 3. recanalization epithelium: proliferated (4-5w) → degenerated lumen : obliterated → vacuolation → recanalized (8w) congenital anomalies: • stenosis • atresia • duplication 4. mesenteries 5. blood supply foregut midgut hindgut celiac A. superior mesenteric A. inferior mesenteric A. II. The Foregut 1. esophagus tracheoesophageal septum elongation recanalization congenital anomalies: • esophageal atresia/ stenosis 2. stomach 1) stomach growth: morphogenesis: fusiform(4w middle) → pouchlike rotation: (6-12w): around its longitudinal axis, 90, clockwise around the ventrodorsal axis, 90, clockwise 2) mesogastrium cavity in dorsal mesogastrium → the omental bursa 21 superior part: infracardiac bursa(心下囊) + superior recess transverse: inferior recess, omental bursa congenital anomalies: • congenital hypertrophic pyloric stenosis 3. duodenum derived from foregut & midgut growth: C-shaped loop, rotation: → retroperitoneal; → right congenital anomalies: • duodenal stenosis / atresia 4. liver & biliary apparatus: 4w early,hepatic diverticulum extended into the septum transversum cranial part: liver primordium caudal part: cystic primordium 1) liver primordium endoderm: hepatic cords, intrahepatic portion of biliary apparatus mesenchyme in septum transversum → C.T. 6w hematopoiesis ; 12 w bile begin formation 2) the ventral mesentery inferior part of the septum transversum → the ventral mesentery a. falciform ligament b. the lesser omentum: hepatogastric ligament + hepatoduodenal ligament c. visceral peritoneum of the liver bare area 3) cystic primordium → gallbladder, cystic duct 4) common bile duct the connecting stalk → common bile duct the entrance: ventral → dorsal aspect of the duodenum 5) congenital anomalies: • extrahepatic biliary atresia 5. pancreas dorsal pancreatic bud rotation & fusion → pancreas ventral pancreatic bud main pancreatic duct : ventral pancreatic duct + dorsal pancreatic duct accessory pancreatic duct congenital anomalies: • anular pancreas 22 III. The Midgut 1. rotation of the midgut loop blood supply: superior mesenteric artery yolk stalk → midgut loop → cranial limb + caudal limb 6-10w, 270, counterclockwise, around the superior mesenteric A. (axis) 1) physiological umbilical herniation formation 6w, midgut loop: → umbilical coelom rotation: around the superior mesenteric A, 90 counterclockwise cranial limb: small intestinal loops caudal limb: cecal diverticulum yolk stalk obliterated 2) return of the midgut to abdomen 10w first: the small intestine returns, posterior to the superior mesenteric A. , occupy the central part of the abdomen then: the large intestines returns, undergoes further 180 counterclockwise rotation last: the cecum, below liver → the right iliac fossa ascending colon appears 3) fixation of the intestines retroperitoneal: duodenum, pancreas, the ascending colon mesentery: duodenojejunal junction to ileocecal junction 2. cecum & appendix 6w,cecal diverticulum cecum appendix: a small diverticulum of the cecum 3. congenital anomalies: • congenital omphalocele(脐膨出) • umbilical hernia(脐疝) • gastroschisis (腹裂) • anomalies of midgut rotation • ileal (Meckel) diverticulum & other yolk stalk remnants IV. The Hindgut 1. fixation of the hindgut retroperitoneal: descending colon 2. the cloaca 1) partitioning of the cloaca (4-6w) urorectal septum: a forklike extensions ventral: urogenital sinus cloaca dorsal: rectum & cranial part of the anal canal 23 7w, perineal body anal membrane (8w end ruptured) cloacal membrane urogenital membrane congenital anomalies: • urorectal septum incomplete separation 2) the anal canal superior 2/3 derived form the hindgut inferior 1/3 derived from proctodeum pectinate line different in blood supply, nerve supply & lymphatic drainage congenital anomalies: • congenital aganglionical megacolon (Hirschsprung disease) 24 DEVELOPMENT OF URIGENITAL SYSTEM intermediate mesoderm → urogenital ridge nephrogenic cord → the urinary system genital ridge → the genital system I. Urinary System 1. kidney & ureters 1) pronephros rudimentary & nonfunctional (1) pronephros 4W beginning 4W end cervical region:nephrotomes (生肾节)→ pronephros → regress (2) pronephric ducts → persist 2) mesonephros interim kidneys (1) mesonephros 4W late caudal region: nephrogenic cord(生肾索)→ mesonephric tubules → regress glomeruli (2) mesonephric (Wolffian) ducts pronephric ducts → mesonephric ducts fused with cloaca 3rd month end → degenerate ♂ a few persist → male genital system 3) metanephros permanent kidneys (1) primordium 5th week ureteric buds (metanephric diverticulum) metanephric blastema (metanephric mass of intermediate mesoderm) reciprocal induction 9w, produce urine a. ureteric buds — collecting system outgrowth from the mesonephric duct bifurcate: ureters → collecting tubules b. metanephric blastema - excretory units derived from the nephrogenic cord metanephric vesicles → metanephric tubules proximal end: → Bowman's capsule + glomeruli → nephrons distal end: contact with arched collecting tubule congenital anomalies: • bilateral renal agenesis oligohydramnios; Potter’s syndrome 25 • unilateral renal agenesis • renal dysplasias • duplication of the ureter • multicystic dysplastic kidney: urinary tract obstruction • congenital polycystic kidney: autosomal recessive condition (2) position change of the kidney ascent of the kidney: pelvis → abdomen rotation: 90°, ventrally → anteromedially congenital anomalies: • ectopic kidneys • horseshoe kidney (3) blood supply of the kidney branches of the common lilac A. → disappear distal end of the aorta → disappear accessory renal A. cranial arterial branches (from the abdominal aorta) → renal arteries 2. bladder & urethra 4-7W urorectal septum cloaca → the urogenital sinus + the anal canal 1) urogenital sinus vesical part → bladder pelvic part + phallic part → urethra 2) bladder vesical part of urogenital sinus enlarge allantois → urachus → median umbilical ligament distal portions of the mesonephric ducts → trigone congenital anomalies: • urachal fistula, cyst, sinus 3) urethra pelvic part: ♂prostatic & membranous urethra;♀: membranous urethra phallic part: ♂: penile urethra;♀: vestibule of vagina congenital anomalies: • exstrophy of the bladder 3. the suprarenal glands mesoderm → fetal cortex → regresses (1yr) neural crest cells → medulla permanent cortex: →zona glomerulosa+ zona fasciculata + zona reticularis (3yr end) 26 II. Genital System • sex determination fertilization SRY gene (sex-determining region of the Y chromosome): testis-determining factor • sex development indifferent stage different stage 1. indifferent stage --- primodium 1) gonads • coelomic epithelium (posterior abdominal wall ) gonadal ridge • underlying mesenchyme • primordial germ cells (1) primordial germ cells endoderm cells in the wall of the yolk sac migration → gonadal ridge (2) gonadal ridge primitive sex cords 2) genital ducts • mesonephric ducts (Wolffian ducts) • paramesonephric ducts (Mullerian ducts): longitudinal invagination of the coelomic epithelium cranial end: opens into the body cavity caudal ends: two fused → uterine canal tip: sinus tubercle 3) external genitalia • genital tubercle → phallus • urethral folds • labioscrotal swellings urethral groove 2. different stage 1) male (1) testis SRY the primitive sex cords: → medullary cords → Sertoli cells (epithelium) primordial germ cells: → spermatogonia mesenchyme: → Leydig cells → testosterone → tunica albuginea (2) genital ducts • mesonephric ducts: ∵ testosterone ∴develop mesonephric ducts → ductus epididymis + ductus deferens mesonephric tubules → ductuli efferentes • paramesonephric ducts: ∵antimullerian hormone (AMH) ∴regress 27 (3) external genitalia testosterone → dihydrotestosterone phallus → penis urethral folds → corpus spongiosum labioscrotal folds → scrotum urethral groove → penile urethra congenital anomalies: • hypospadias • epispadias (4) descent of the testes gubernaculums posterior abdominal wall → inguinal canal → scrotum peritoneal sac → vaginal process →tunica vaginalis & proximal part obliterated congenital anomalies: • congenital inguinal hernia;hydrocele failure of closure of the processus vaginalis • cryptorchidism • ectopic testes 2) female (1) ovary no Y chromosome, no SRY primitive sex cords → regress surface epithelium → secondary sex cords (cortical cords)+ oogonia → follicles mesenchyme → stromal cells (2) genital ducts mesonephric duct: no testosterone → regress paramesonephric duct: no AMH → develop paramesonephric duct → uterine tube + uterovaginal primordium uterovaginal primordium → corpus and cervix of the uterus + upper portion of vagina sinus tubercle induced → sinovaginal bulbs (from urogenital sinus) sinovaginal bulb → vaginal plate → vagina (lower 2/3) hymen congenital anomalies: • abnormal development of the uterus • absent of the vagina & uterus • vaginal atresia • imperforate hymen 28 (3) external genitalia genital tubercle → clitoris urethral folds → labia minora labioscrotal swellings → labia majora (4) descent of the ovaries abdominal → pelvic gubernaculums → ovarian ligament + round ligament of uterus 3) congenital anomalies in sex differentiation hermaphrodites phenotype ≠ Epi type; gonad ≠ external genitalia (1) true hermaphroditism ovary & testes / ovotestes; external genital is ambiguous (2) pseudohermaphrodites • female pseudohermaphroditism 46, XX; chromatin-positive nuclei (sex chromatin, Barr body) ovary external genitalia: masculinization congenital adrenal hyperplasia (produced by suprarenal gland ) • male pseudohermaphrodites 46, XY chromatin- negative nuclei internal and external genitalia variable inadequate production of androgenic hormones & AMH • androgen insensitivity syndrome (testicular feminization syndrome); 46, XY testes external genitalia are female virgina ends blindly; uterus & uterine tube absent lack of androgen receptors 29 DEVELOPMENT OF CARDIOVASCULAR SYSTEM Three features: • Developing early • Mostly from mesoderm • Obvious changes after birth I. Development of primordial cardiovascular system 1. Development of Early Blood Vessels (angiogenesis) 3w Extraembryonic mesoderm of the yolk sac, connecting stalk and chorion → blood islands → canalized → vessels endothelia and primitive blood cells 13-15d: extraembryonic angiogenesis 2d later: intraembryonic angiogenesis 2. Development of Primitive Heart Tube Primordium: Cardiogenic area paired angioblastic cord → endocardial heart tubes Intraembryonic coelom → pericardial coelom Lateral fold: 2 heart tubes →single heart tube Head fold: cranial → caudal & ventral 3. Primitive cardiaovascular system Form: middle of 3w Function: beginning of 4w Three separate circulations: vitelline, chorionic, and intraembryonic. II. Development of the heart 1. Primodium: Endocardial heart tube 1) Origin: splanchnic mesoderm and neural crest cells Endothelium → endocardium Cardiac jelly → subendocardial tissue Primordial myocardium (Myoepicardial mentle) →myocardium, epicardium 2) Endocardial heart tube fusion from cranial to caudal at 4w Dorsal mesocardium → transverse pericardial sinus 2. Looping of the heart Truncus arteriosus Bulbus cordis Bulboventricular loop (cephalic portion bends ventrally, caudally and slightly to the right) Ventricle Atrium → dorsocranially and bulges laterally on each side of bulbus Sinus venosus Congenital anomalies: Dextrocardia; Acardoa; Ectopic cordis 30 3. Partitioning of the heart 1) Division of atrioventricular canal Subendocardial tissue → 2 endocardial cushions → fuse → right and left canals 2) Partitioning of the atria Septum primum → endocardial cushions → foramen primum Septum primum absorbed → foramen secundum → foramen primum closing Septum secundum → cover the foramen secundum → foramen ovale Congenital anomalies: Atrial septal defects (ASD) 3) Repositioning of the sinus venosus Center ↓ Left to right shunts Right horn enlarged ―――――――― Left horn diminished ↓ ↓ Smooth part of right atrium Coronary sinus Primordial RA → rough part Primordial LA → left auricle (primordial pulmonary vein → smooth part of LA) 4) Partitioning of the ventricles Primordial interventricular septum (IVS) 5w → Muscular part of IVS IV foramen 7w Congenital anomalies: Ventricular septal defects (VSD): most common, especially membranous part 5) Partitioning of the outflow tract of the heart Right and Left Truncal ridges + Bulbar ridges ↓ fuse aorticopulmonary septum ↓ 180o spiraling pulmonary trunk → right ventricle aorta → left ventricle Bulbus cordis → Conus arteriosus of RV,Aortic vestibule of LV Truncus swellings → semilunar valves Congenital anomalies: Truncus arteriosus:Accompanied by VSD Transposition of the great arteries Unequal division of the truncus ateriorsus Tetralogy of Fallot:pulmonary stenosis,VSD,overriding aorta,AV hypertrophy 4. Conducting system of the heart Right wall of sinus venosus → Sinuatrial node (5w) Left wall of sinus venosus → AV node & bundle 31 III. Development of arteries Vitelline artery Aortic sac → Aortic arches → Dorsal arota →30 pairs intersegmental arteries Umbilical artery 1. Vitelline artery Celiac artery (truncus coeliacus), A. Mesenterica superior, A. Mesenterica inferior 2. Umbilical artery Proximal parts → A. iliaca interna, A. vesicales superiores Distal parts → Lig. Umbilica media 3. Intersegmental arteries Neck → A. vertebralis (7th →A. subclavia) Thorax → A. intercostalis Abdomen → A. lumbar (5th → A. iliaca commnis) Sacral region → A. sacrales laterals 4. Aortic arches 1)1st → A. maxillary, A. carotis externa nd 2) 2 → A. stapedia rd 3) 3 proximal → A. carotis communis distal → A. carotis interna (along with dorsal aortae) th 4) 4 left → arch of aorta right → A. subclavia dextra (along with dorsal aorta & 7th IS artery) left 7th IS artery → A. subclavia sinistra th 5) 5 → degenerate 6) 6th left proximal → A. pulmonalis sinistra distal → ductus arteriosus (lig. Arteriosum) right proximal → A.pulmonalis dextra distal → degenerate Congenital anomalies: Coarctaton of the aorta (mostly Juxtaductal coarctation); Double aortic arch; Right arch of aorta; Anomalous right subclavian artery IV. Development of veins Vitelline veins Sinus venosus ← Umbilical veins Common cardinal veins (CCV) ← anterior (ACV) posterior (PCV) 1. Vitelline veins Hepatic vein ←Cranial R. Cranial L → Middle R → Hepatic sinusoids ← Middle L Caudal R. → Anastomotic network ← Caudal L ↓ Portal vein 32 regressed 2. Umbilical veins Regressed Cranial R. ---------- Cranial L. → Regressed Caudal R ----------- Caudal L. → Ductus venosus Umbilical vein 3. Cardinal veins L. brachiocephalic v. ↑ Anastomotic shunt Coronary sinus Regressed ACV L. ACV R. → SVC ↓ ↓ ← CCV L. → Sinus venosus ← CCV R. ↑ ↑ ← PCV L. PCV R.→ Root of Azygos v. Iliac Anastomosis ↓ Common iliac v. Subcardinal veins → L. Renal v., Superenal v., Gonadal v., IVC Anastomosis → L. Renal v., IVC Supracardinal veins → Azygos v., Hemiazygos v, IVC 4 segments of inferior vena cava Hepatic segment ← Heptic vein Prerenal segment ← R. subcardinal v. Renal segment ← Anastomosis Postrenal segment ← R. supracardinal v. Anomalies: Double SVC; Left SVC V. Fatal and neonatal circulation 1. Fetal circulation Placental circulation with umbilical A. & V. Ductus venosus Foramen ovale Ductus arteriosus 2. Neonatal circulation Pulmanary circulation Ductus venosus → Lig. venosus Foramen ovale → Oval fossa Ductus arteriosus → Lig. arteria Congenital anomalies: Patent Ductus Arteriosus (PDA) 33 DEVELOPMENT OF THE NERVOUS SYSTEM I. Origin of the nervous system 1. inducer: notochord and paraxial mesoderm proliferation invagination 2. ectoderm cells (overnotochord) neural plate neural groove & neural fold closure neural tube → CNS 4th pair of somites cranial 2/3 → brain caudal 1/3 → spinal cord rostral (anterior) neuropore: closed by 25-26 days caudal (posterior) neuropore: closed by 27-28 days 1) lumen of the neural tube → ventricular cavities of the brain & central canal of the spinal cord 2) wall of the neural tube (neuroepithelium) → nervous tissue 3) mesenchyme surrounding the neural tube → meninges 3. neural crest → PNS II. Histological differentiation of cells in CNS early neuroblasts (apolar ~ → bipolar ~ → unipolar ~ ) → neuroepithelial cells neurons last → astroblasts → astrocytes ependymal cells late glioblasts → oligodendroblasts → oligodendrocytes ventricular zone (ependymal layer) intermediate zone (mantle layer) axons & glial cells → marginal zone (layer) III. Development of the spinal cord 1. the appearance of the spinal cord in adult 2. the development of the spinal cord 1) the development of the spinal cord from caudal 1/3 of the neural tube (1) lumen of the neural tube → central canal of the spinal cord (2) mantle layer → gray matter of the spinal cord proliferation and differentiation of the neuroepithelial cells in the mantle layer causes the formation of: a. alar plates (dorsal, sensory)→ dorsal gray columns (horns) b. roof plates sulcus limitans c. basal plates (ventral, motor)→ ventral gray columns (horns) & lateral (intermediate) columns (horns) d. floor plates (3) marginal layer → white matter of the spinal cord 34 2) development of spinal ganglia and nerves (1) neural crest cells → bipolar neuroblasts → unipolar afferent neuron → spinal ganglia (2) the peripheral processes → spinal nerves (3) the central processes → the dorsal roots of the spinal nerves (4) neural crest cells → satellite cells & schwann cells 3) development of spinal meninges mesenchyme surrounding the neural tube → meninges (1) external mesenchyme → dura mater (2) neural crest cells + internal mesenchyme → leptomeninges (arachnoid mater + pia mater) subarachnoid space & cerebrospinal fluid (CSF) 4) positional changes of the spinal cord and formation of the cauda equina because the vertebral column and dura mater grow more rapidly than the spinal cord, the caudal end of the spinal cord lies at the level of (1) 1st sacral lumbar vertebra at 24 weeks prenatal (2) 2nd to 3rd lumbar vertebra in the newborn (3) the inferior border of 1st lumbar vertebra in the adult (4) nerve roots inferior to the end of the spinal cord form a sheaf --- cauda equina 5) myelination of nerve fibers 4th months prenatal to 1st year postnatal schwann cells & oligodendrocytes 6) congenital anomalies of the spinal cord spina bifida: defective closure of the neural tube (NTD), meninges, vertebral arches, muscles and skin (1) spina bifida occulta (隐性脊柱裂) (2) spina dermal sinus (脊皮窦) (3) spina bifida cystica (囊性脊柱裂) a. spina bifida with meningocele (脊柱裂合并脊膜膨出) b. spina bifida with meningomyelocele (脊柱裂合并脊膜脊髓膨出) sphincter paralysis (saddle anesthesia, lumbosacral meningomyelocele) c. spina bifida with myeloschisis (脊柱裂合并脊髓裂) IV. Development of the brain 1. The appearance of the brain in adult 2. The development of the brain 1) primary brain vesicles (4th week) midbrain flexure & cervical flexure (1) forebrain (prosencephalon) (前脑泡) (2) midbrain (mesencephalon) (中脑泡) (3) hindbrain (rhombencephalon) (菱脑泡) 2) secondary brain vesicles (5th week) 35 pontine flexure (1) forebrain telencephalon (端脑) + diencephalon (间脑) (2) midbrain mesencephalon (中脑) (3) hindbrain metencephalon (后脑) + myelencephalon (末脑) 3) the development of brain vesicles (1) myelencephalons (末脑) → medulla oblongata canal → central canal of the spinal cord a. caudal part alar plate → gracile nuclei + cuneate nuclei (close part) ventral area → pyramids canal → lower part of 4th ventricle b. rostral part alar plate → 4 sensory nuclei (open part) basal plate → 3 motor nuclei c. pia mater → tela choroidea → choroid plexus roof plate (2) metencephalon (后脑) a. canal → upper part of 4th ventricle b. alar plate → 3 sensory nuclei & pontine nuclei c. dorsal part of alar plate → rhombic lip→ cerebellar plate (fuse)→ cerebellum d. basal plate → 3 motor nuclei e. ventral area → pons (3) mesencephalon (中脑) a. canal → cerebral aqueduct b. alar plate → tectum (顶盖) → superior colliculi (上丘) + inferior colliculi c. basal plate → tegmentum (被盖) → red nuclei etc (4) diencephalon (间脑) a. canal → posterior part of 3rd ventricle b. roof plate → pineal body epithalamus c. alar plate → thalamus hypothalamus → pituitary gland d. the development of the pituitary gland neuroectoderm floor of the diencephalons ectodermal roof of the ↓ stomodeum neurohypophysial bud ↓ ↓ hypophysial pouch (Rathke Infundibulum pouch) ↓ ↓ Neurohypophysis adenohypophysis pituitary gland craniopharygioma (颅咽管瘤) 36 e. pia mater → tela choroidea → choroid plexus roof plate (5) telencephalon (端脑) one median portion and two lateral diverticula lamina terminalis (终板) rd a. canal → anterior part of 3 ventricle, lateral ventricle b. floor part → corpus striatum (纹状体) c. pia mater → tela choroidea → choroid plexus roof plate d. CSF circulation e. phylogeny (种系发生) of cerebrum archeopallium (古皮质), palaeopallium (旧皮质), neopallium (新皮质) 4) congenital anomalies of the brain (1) cranium bifidium (颅裂) (2) cranial meningocele (脑膜膨出) (3) meningoencephalocele (脑膜脑膨出) (4) anencephaly (无脑畸形): defective closure of the neural tube (NTD), (5) hydrocephalus (脑积水) (6) hydranencephaly (积水性无脑畸形) (7) microcephaly (小头畸形) (8) holoprosencephaly (前脑无裂畸形) V. Development of the PNS originate from the neural crest - 37 -