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Periods of Human Development Preorganogenic Embryonic Fetal Spermatocyte Oocyte 2C 2N 1C 1N 1C 1N Sperm • 200-300 million ejaculated into female reproductive tract • Survive ≥ 24 hr • Undergo capacitation to become fertile - requires ≈ 7 hr in female reproductive tract - removes glycoprotein and plasma proteins from plasma membrane Development of Oocyte and Follicle FSH Estrogen LH secretion Proliferative phase Pituitary Uterine endometrium Development of Oocyte and Follicle LH LH surge LH surge • Increases levels of maturation promoting factor • Stimulates oocyte completion meiosis I • 1st polar body formed • Secondary oocyte arrests in metaphase II • Stimulates ovulation • Stimulates luteal reaction in granulosa and theca cells • Increases progesterone synthesis • Induces secretory phase in endometrium Corpus Luteum With Fertilization Without Fertilization HCG secreted from trophoblast Cells degenerate Corpus luteum of pregnancy formed Secretes high levels of progesterone Corpus albicans formed Ovulation • LH surge • Increases collagenase activity • Increases prostaglandin-induced contractions of ovary and uterine tube • Corona radiata forms from cumulus oophorus • Fertilization occurs in the ampulla within 12-24 hr Fertilization Acrosome reaction • Release of enzymes (acrosin) • Required for digestion through zona pellucida Sperm bind ZP3 receptors Capacitation required for penetration of corona radiata Cortical reaction • Release of lysosomal enzymes Zona reaction • Inactivates sperm receptors • Prevents polyspermy Fusion of sperm & oocyte plasma membranes • Involves integrins (oocyte) and disintegrins (sperm) • Stimulates oocytes completion of meiosis II (2nd & 3rd polar body formed) • Sperm mitochondria degraded • Sperm centrioles involved in subsequent cell division Fertilization • Restores diploid # chromosomes • Determines sex of embryo Immediately upon fertilization • Pronuclei form = pronuclear stage • DNA replication occurs Æ 4C, 2N • Chromosomes mix = syngamy • Cleavage occurs Æ 2 cells Morulation Day 1-3 • Blastomeres form • Zona pellucida persists • Morula = 16 cell embryo (each cell 1/16 mass of ovum) • Compaction occurs due to formation of tight junctions • Segregation of cells • Inner cell mass Æ embryo • Outer cell mass Æ trophoblast • Gap junction communication within each group Blastocyst formation (day 4-6) Implantation (day 6-9) • Zona pellucida degenerates • Blastocyst cavity formed • Embryoblast Æ embryo • Trophoblast Æ placenta • Trophoblasts invade endometrium • Integrins on trophoblasts bind ECM • Laminin Æ attachment • Fibronectin Æ migration Events in Week 1 • Ovulation • Fertilization • Cleavage • Morulation • Blastocyst formation • Implantation Menstrual Cycle • Menstrual phase ≈ d1-5 • Proliferative (follicular) phase • Ovulation ≈ d11-14 • Secretory (progestational) phase begins 2-3 d after ovulation With Fertilization • HCG from trophoblast maintains corpus luteum • Progesterone from corpus luteum stimulates gravid phase of endometrium Pituitary Regulation of Ovary and Uterus Week 2: Formation of Bilaminar Germ Disc ≈ day 7.5 • Embryoblast Æ Epiblast and Hypoblast • Trophoblast Æ Cytotrophoblast and Syncytiotrophoblast • Cytotrophoblast Æ Syncytiotrophoblast • Amniotic cavity forms in epiblast • Decidua reaction: uterine glands secrete glycogen and mucous ≈ day 9 • Trophoblastic lacunae form in syncytiotrophoblast • Blastocyst cavity Æ Primitive/primary yolk sac • Cytotrophoblast layer extends around abembryonic pole • Exocoelomic membrane formed ≈ day 12 • Uteroplacental circulation established by invasion of maternal vasculature • Extraembryonic mesoderm forms • Extraembryonic coelom forms within mesoderm layer • Coelom separates mesoderm into 2 layers = splanchnic and somatic ≈ day 13 • Syncytiotrophoblast surrounds embryo and primary villi form • Hypoblast migrates to line inside of primitive yolk sac Æ Secondary yolk sac • Extraembryonic coelom Æ Chorionic cavity • Extraembryonic somatic mesoderm Æ Chorionic plate • Embryo suspended by connecting stalk Ectopic Implantation Sites Implantation in Uterine Tube Implantation in Uterorectal Pouch Bilaminar Germ Disc at End of Week 2 Week 3 Gastrulation Forms Trilaminar Germ Disc and Notochord • Epiblasts migrate • into primitive streak and primitive pit • Epiblasts differentiate to form • 3 embryonic tissue types • ectoderm • mesoderm • endoderm • Notochord Formation of Notochord Specification of Cranial-Caudal and Dorsal-Ventral Axes • Anterior visceral endoderm (AVE) present before gastrulation • expresses factors that specify the cranial region • Nodal expression initiates and maintains the primitive streak • BMP-4 (hatched area) is expressed throughout embryo • with FGF, BMP-4 specifies the ventral and lateral mesoderm • BMP activity is antagonized (blocked) to induce dorsal mesoderm • goosecoid, chordin, noggin, follistatin expression by node induce notochord, somites and somitomeres in cranial region • Brachyury (T) expression in mid and caudal regions induces dorsal mesoderm Specification of Midline and Left-Right Body Axes • Notochord expresses sonic hedgehog (SHH) and Brachyury (T) genes at the midline • Node and primitive streak express FGF8 which controls nodal expression on left side of body Embryo at End of Week 3 Development of Early Placental Villi • Placental barrier • Syncytiotrophoblast • Basal lamina • Mesoderm • Basal lamina • Endothelial cell • Where is maternal blood? • Surrounding syncytiotrophoblast • Where is fetal blood? •Inside villous capillaries Week 3 • Notice cranial-to-caudal gradient of development • What is happening during this period? Gastrulation and notochord formation • How big is the embryo? ≈ 1 mm length Week 3 Notochord • Induces ectoderm Æ neural plate • Induces mesoderm Æ somites Process of Neurulation • Edges of neural plate elevate Æ neural folds and neural groove • Folds fuse Æ neural tube • Neural crest • undergoes epithelial to mesenchymal transition • dissociates from neural tube • migrates throughout body Process of Neurulation • BMP-4 induces ectoderm Æ epidermis • Blocking BMP-4 activity induces formation of neural tissue • Node, notochord & prechordal mesoderm secrete BMP-4 antagonists • Expression of WNT and FGF required to differentiate immature forebrain/midbrain type tissue into hindbrain Week 4 Fusion of neural tube begins in cervical region and proceeds in both cephalic and caudal directions Week 4 • Closure of neuropores • d25 and d27 • essential to CNS development • Folding • cephalocaudal • lateral Retinoic acid regulates cranial-to-caudal axis • Controls specification of neural tissue type • Controls gradient of Homeobox (Hox) gene expression Mesoderm Differentiation (Intra-Embryonic) • Paraxial mesoderm Æ somites (segmented) • Intermediate mesoderm Æ urogenital system (partially segmented) • Lateral plate mesoderm splits • Somatic continuous with extraembryonic somatic • Splanchnic continuous with extraembryonic splanchnic • Intraembryonic coelom continuous with extraembryonic coelom Somite Differentiation • Cranial-to-caudal formation d20-d35 • 42-44 total pairs some degenerate • Sclerotome Æ bone and cartilage • Dermomyotome • Dermatome Æ dermis • Myotome Æ skeletal muscle Regulation of Mesoderm Differentiation • Notochord: SHH • Neural tube: SHH, WNT, NT3 • Ectoderm: BMP-4, WNT • Lateral plate: BMP-4 • Sclerotome: Pax1 • Dermomyotome: Pax3 • Myotome: • MyoD (limb & body wall) • Myf5 (back) Formation of Blood Vessels • Vasculogenesis • Form from blood islands •Angiogenesis • Sprout from existing vessels • FGF induces hemangioblast Æ blood islands Æ hematopoietic stem cells and angioblasts • VEGF • Induces angioblasts Æ endothelial cells and vessels • Induces angiogenesis Cephalocaudal Folding of Embryonic Disc • Driven by CNS growth • Head & tail fold • Endoderm folded inside body • foregut • midgut • hindgut • Yolk sac connected by vitelline duct Lateral Folding of Embryonic Disc • Driven by growth of somites • Lateral plate mesoderm fuses at anterior midline • Vitelline duct persists at midline (in midgut) Formation of Endoderm-lined Tube • Buccopharyngeal and cloacal membranes rupture • Umbilical cord formed • vitelline duct from midgut • allantois from cloaca of hindgut • blood vessels Day 28 Week 5 Week 6 Week 11 Week 12 Month 7 Fetus would survive