Periods of Human Development

Preorganogenic FetalEmbryonic

Spermatocyte Oocyte

1C1N

2C2N

1C1N

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

EstrogenLH secretion Pituitary

Proliferativephase

Uterineendometrium

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 WithoutFertilization

HCG secreted from trophoblastCells degenerate

Corpus luteumof pregnancy formed Corpus albicans

formed

Secretes high levelsof progesterone

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

FertilizationCortical reaction• Release of lysosomal enzymes

Acrosome reaction• Release of enzymes (acrosin)• Required for digestion through zona pellucida

Sperm bindZP3 receptors Zona reaction

• Inactivates sperm receptors• Prevents polyspermy

Capacitationrequired for

penetration of corona radiata

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 4C, 2N• Chromosomes mix = syngamy• Cleavage occurs 2 cells

MorulationDay 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 embryo• Outer cell mass trophoblast• Gap junction communication within each group

Blastocyst formation (day 4-6)

• Zona pellucida degenerates• Blastocyst cavity formed• Embryoblast embryo• Trophoblast placenta

Implantation (day 6-9)

• Trophoblasts invade endometrium• Integrins on trophoblasts bind ECM

• Laminin attachment• Fibronectin migration

• Ovulation• Fertilization• Cleavage• Morulation• Blastocyst formation• Implantation

Events in Week 1

With Fertilization• HCG from trophoblast maintains

corpus luteum• Progesterone from corpus luteum

stimulates gravid phase of endometrium

Menstrual Cycle• Menstrual phase ≈ d1-5• Proliferative (follicular) phase• Ovulation ≈ d11-14• Secretory (progestational) phase

begins 2-3 d after ovulation

Pituitary Regulation of Ovary and Uterus

Week 2: Formation of Bilaminar Germ Disc

≈ day 7.5

• Embryoblast Epiblast and Hypoblast

• Trophoblast Cytotrophoblast and Syncytiotrophoblast• Cytotrophoblast Syncytiotrophoblast

• Amniotic cavity forms in epiblast

• Decidua reaction: uterine glands secrete glycogen and mucous

≈ day 9

• Trophoblastic lacunae form in syncytiotrophoblast

• Blastocyst cavity 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 Secondary yolk sac• Extraembryonic coelom Chorionic cavity

• Extraembryonic somatic mesoderm 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 3Gastrulation 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 neural plate• Induces mesoderm somites

Process of Neurulation

• Edges of neural plate elevate neural folds and neural groove• Folds fuse neural tube• Neural crest

• undergoes epithelial to mesenchymal transition• dissociates from neural tube• migrates throughout body

Process of Neurulation

• BMP-4 induces ectoderm 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 ofHomeobox (Hox) geneexpression

Mesoderm Differentiation

(Intra-Embryonic)

• Paraxial mesoderm somites (segmented)• Intermediate mesoderm urogenital system (partially segmented)• Lateral plate mesoderm splits

• Somatic continuous with extraembryonic somatic• Splanchnic continuous with extraembryonic splanchnic• Intraembryonic coelom continuous with extraembryonic coelom

SomiteDifferentiation

• Cranial-to-caudal formationd20-d35

• 42-44 total pairssome degenerate

• Sclerotomebone and cartilage

• Dermomyotome• Dermatome

dermis• Myotome

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 hemangioblastblood islandshematopoietic stem

cells and angioblasts• VEGF

• Induces angioblastsendothelial 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