By Week 4

• all 3 germ layers (gastrulation
• CNS developing(neurulation)
• mesoderm differentiated 

Weeks 3-8s

• knwon as embryonic period
• sees establishment of all major organ systems

Weeks 9-38

• Known as fetal growth period
• longest period of development
• continued differentiation of organ system
• fetal growth in size and weight 

Crown-Rump Length (CRL)

• distance from vertex of head to midpoint of buttocks
• typical means to measure age of fetus(1st trimester)
• measured using ultrasound
• in 2nd and 3rd trimesters more structures are developed to estimate age 

Fetal Growth Week 9

• 5cm CRL
• Head is half of embryonic Length
• eyelids still fused but have definitive features
• ears have definitive features
• urine begins to be produced and secreted

Fetal Growth Week 12

• 9cm CRL
• Size nearly doubled from week 9
• primary skeletal ossification centers present
• male and female genetalia are differentiated

Fetal growth: 13-16 weeks

• CRL 16 weeks, rapid growth
• limbs begin to exhibit coordinated movnts
• not yet strong enough to be felt
• bones visible in ultrasound
• eye movements begin
• sex recognizable(14wks) and ovaries differentiat(16wks)

Fetal Growth: 17-20 weeks

• relativly slow growth
• relative limb lengths established and first movt felt
• quickening(mean birth in 147 days)
• eyebrowsn and hair by wk 20
• utures by wk 18 and testes begin to descend
• brown fat for heat production

Fetal Growth: 21-25 Weeks

• doubles in weight, 23cm CRL(24wk)
• REM and blink-startle response begins
• lungs begin to develop alveoli(cant breath yet)
• fingernails(24wks)
• premature can survive but usually dont

Fetal Growth: 26-29 Weeks

• 27cm CRL
• Lungs capable of breathing(gas exchange)
• CNS can direct rhythmic breathing
• eyelids open by 26wks
• subcantaneous fat and erythropoeisis in bone marrow present
• prematures often survive after 26wks

Fetal Growth: 30-38

• premies usually survive and may reach normal birth weight
• pupillary light reflex (wk 30)
• firm grasp (35wks)
• plump by week 34(14 grams fat per day in last few weeks)

Full Term Measurements

• 36 cm CRL 
• 3400 grams
• 16% of weight is fat 
• weight mostly added in 3rd trimester and height in 2nd trimester
• growth is allometric rather then isometric

Expected Date of Delivery

(EDD)

• 266 days or 38 wks from fertilization
• wide range of variation
• 12% born 1-2 weeks late
• ultrasound and CRL during 1st trimester can help gauge 

Naegales Rule

• count back 3 months from LNMP
• add 1 year and then add 7 days
• works well w/ women w/ regular cycles blocking
• irregular cycles and imphatation blocking can cause 2-3 weeks miscalculation

Insulin-Like Growth Factor

• stimulates fetal growth
• HGH stimulates postnatal growth

Intrauterine Growth Retardation

• cause by cigs, alcohol, drugs, poor nutrition, and genetic factors

Birth Defects

• congenital malformations or anomalies present at birth
• occur in 4-6% of births
• accounts for 20% of infant deaths

Malformations

(Birth Defect)

• errors in genetic programming/ tissue formation

Deformations

(Birth Defects)

• when genetically normal tissues are forced into abnormal shapes by mechanical/environmental forces
• example is club foot from pressure of womb

Disruptions

(Birth Defect)

• occur when normal tissues experience a specific insult
• example is limb reduction(missing hand)

Syndrome 

• group of anomolies occuring together with a common cause

Teratogens

• factors that can cause birth defects
• include genotype impact, age of fetus of exposure, dose/duration
• thalidomide in 1960s first widespread one

Fetal Alcohol Syndrome (FAS)

• documented that maternal ingestion of alcohol causes congenital abnormalities, mental retardation and growth deficiency
• critically imports Nervous system and even moderate consumption leads to it
• 1 in 100 live births
• can contribute to IUGR

Retinolic Acid 

• vitamin A derivatives can cause malformations
• teratogenic to fetus
• isotetinoin in acne medicine caused malformation

Amniocentesis

• uses syringe to extract amniotic fluid
• best after wk 12
• can detect several genetic disorders

Fertilization

• sperm and oocyte fuze to become a zygote 
• process takes a whole day
• usually happens in the ampulla of uterine tube

Morula

• forms about 3 days after fertilization
• ball of 12 - 16 cells
• the cells are touching but are not in tight contact

Blastocyst 

• hollow ball that consists of outer trophoblast cells and inner cell mass(embryoblasts)
• implants on uterine wall about day 6
• 50% fail to implant 
• abnormal zygote usually fails to implant
• embryoblasts are source of embryonic stem cells

Bilaminar embryonic Disk

• contains embryoblast cells
• half hypoblasts half epiblasts
• amiotic cavity on top and yolk sac underneath
• forms during week 2 

Sinusoids and Lacuna

• maternal blood vessels that begin to establish uteroplacental circulation when the blastocyst impants on the uterine wall

Syncytiophoblast 

• produces a hormone that is used for pregnancy testing

Chorionic Cavity

• begins to form around day 13
• the cavity encloses almost completely around the yolk sac and the amiotic cavity
• where it doesnt conect is the connecting stalk the later leads to the umbilical chord

Gastrulation

• early in week 3
• 3 germ layers formed
• ectoderm and from that the mesoderm and endoderm
• starts at the primitive streak
• primitive streak is at caudal part of midline

Notechord

• made of mesoderm cells 
• supports embryo
• becomes vertabrae later 

Neurulation

• forms a neural tube
• this structure later leads to Central nervous system
• ectodermal cells migrate to form neural tube and the neural crest
• neural crest becomes PNS

Sacrococcygeal Teratoma

• tumor near anus 
• develops if the primitive streak does not disapear after week 4 of gestation 
• firm to touch
• not to be confused with fluid filled herniations

Somites

• formed from parixial mesoderm that is on either side of notechord
• looks like a string of beads on either side of notechord
• starts cranially

Mesoderm Developmental

Segments

• paraxial mesoderm
• intermediate mesoderm
• Lateral (Plate) Mesoderm

Paraxial Mesoderm

• located next to the developing notechord/neural tube
• it will develop into somites
• somites give rise to cells that form vertebrae, ribs, mast cells, skeletal muscles and dermis of dorsal skin

Intermediate Mesoderm

• develops lateral to paraxial mesoderm and will initially connect paraxial and lateral mesoderm

Lateral (Plate) Mesoderm

• develops laterally and will eventually contact extraembryonic mesoderm
• lateral mesoderm divides into somatic(parietal) and splanchic(visceral) layers

Bone Morphogenetic Protein (BMP)-4

• vetralizes mesoderm
• ventral mesoderm will develop into intermideate(im) and lateral plate mesoder(IPM)

Blocking BMP-4

• dorsalizes mesoderm
• includes mesoderm surrounding the notechord and paraxial mesoderm(somites)
• antagonist include goosecoid, chordin, noggin, and follistatin

Wnt

• expressed from dorsal neural tube 
• regulates expression of Pax3(identifies the dermatone)
• regulate Wyf5 and MyoD(initiating dorsmedial development of epexial muscles)
• initiates limb and body wall muscles 
• Bmp4 also present

Somitomeres

• organized segments of paraxial mesoderm (wnt)
• develop initially in cephalic region and new ones develop in both directions
• in head do not differentiate and contribute to head (mesenchyme)
• from occipital down they differentiate into somites

Somite Proliferation

• paired cuboidal blocks(wk 3)
• 1st pair of somites appear in the cervical region (day 20)
• 3-4 pairs develop per day until 5 wks 
• 42 -44 pairs develop (4 occ, 8 cerv, 12 thor, 5 lumb, 5 sac, 8 coc)
• last 5-7 reabsorb while rest become vertbarl skeleton
• # of somites can be used to guess age

Somite Differentiation

• ventral medial cells in somites lose organization and migrate to surround notechord
• loosely organized cells will become sclerotome and form vertebral skeleton 
• cells in dorsolateral region differentiate and become dermomyotome that become skin of back, muscles of limb and body wall
• each somite forms a sclerotome, myotome and dermatone and has segmental nerve (wnt involved)

Sonic Hedgehog

• Shh
• regulate of somite differentiation
• from neural tube and notechord
• induces sclerotome formation

Neurotrophin-3 (NT-3)

• expressed in neural tube
• directs formation of dermis in middle of the dermomyotome

Skeletal Development

• neural crest-most of the skull
• lateral (plate) mesoderm-appendicular skeleton
• somites- axial skeleton (minus most of skull)

Sclerotome

• bone producing portion of somite
• technically produces cartillage that turns into bone

Spina Bifida

• Failure of two vertebral arches to fuse
• happens in wk 4 when schlerotomes from left and right unite around notechord and spinal chord
• more serious if accompanied by failure of the neural tube to close

Date of First evidence of Limb Buds

• day 26(end of 4th week)
• major features of limb by end of 8th week
• forelimb buds proceed hind limb buds and both by day 28

Carnegie Stages

• standardized set of embryonic stages based on appearence of structures during development

Origin of Limb Buds

• formed by core of somatic lateral plate mesoderm that is covered in ectoderm
• limb bud elongates by proliferatin of mesenchyme in proximal-distal discretion

Lateral Plate mesoderm

Limb Bud Contribution

• skeleton, blood vessels, and connective tissue

Neural Crest Limb Bud

Contribution

• gives rise to sensory nerves, schwann cells and pigment cells

Hand and Foot Development

• hand plates form in week six(foot plates week 7)
• mesenchyme in plates condense to form digital rays
• apoptosis of webbing results in fingers and toes by week 8

Limb bending and rotation

• 6th week limb buds bend at knee and elbow
• both knee and elbow face posteriorly 
• 7th week joints rotate to current anatomical position

Limb Axes in Development

• thumb/big toe anterior and 5th digit posterior
• palm or sole ventral and back of hand/foot dorsal

Homeobox (Hox) genes

• highly conserved
• mutations cause large-scale changes
• crucial for establishing Ant-Post axis in body
• limb position constant relative to Hox
• mutation in Hox can change position of limbs

Fibroblast Growth Factor (FGF) 10

• capable of stimulating cell growth, proliferation and differentiation
• provides signal for limb bud initiation
• experimental addition of FGF10 adds limbs to body walls
• FGF10 KO has no limbs

TBX (TBOX) 4 and 5

• tightly conserved transcription factors that regulate developmental process
• TBX4 specifies hind limb during development
• TBX5 specifies fore limb during development

TBX, HOX and FGF steps

• HOX9 initiaties TBX4 and TBX5
• TBX genes initiate FGF10 expression
• FGF10 stimulates ectoderm to express FGF8

Apical Ectodermal Ridge (AER)

• distal tip of limb bud covered in ectoderm
• expresses FGF4 and FGF8 that establish proximal-Distal growth
• progress zone is behind AER and is a rgeion of proliferating mesenchyme cells

Zone of Polarizing Activity (ZPA)

• group of mesodermal cell sin posterior edge of Limb bud
• secretes Sonic Hedgehog(Shh)
• forms a gradient that establishes anterior-posterior axis
• exposure makes posterior compartment

Wnt7a

• initiates dorsal structures
• activates imx-1 (homeobox gene)

HoxA and HoxD Paralouges

• second wave of Hox that establish proximal-distal structures
• Shh stimulates the expression of these
• there mechanism is not fully known

Bone Morphogenetic Proteins

• signaling molecules involved in inducing several strucures during development
• mediates the elimination of webbing through apoptosis
• BMP-4 and 2

Time of Developmental Limb 

Problems

• usually occur in weeks 4 through 8 of development
• only get bigger after week 8

Amelia and Meromelia

• abscence (amelia) or partial abscence (meromelia) of limb
• supression of limb bud in week 4 (amelia)
• arrest or disturbance of limb bud growth during wk 5(meromelia)

Thalidomide

• used to treat morning sickness in the 60's
• disrupts limb development
• distal process of limbs attached to shoulder
• mechanism not know but used in cancer research now

Holt-Oram Syndrome

• autosomal dominant disorder affecting upper limb development
• mutation in TBX5
• effect some/all bones of forelimb
• about 75% also have heart problems

Al-Awadi...(AARRS)

• aautosomal recessive disorder linked to wnt7A
• wnt71 expersed in dorsal ectoderm
• phocomelia (abscence of fibula and ulna), limb/pelvis aplasia and others

Nail-Patella Syndrome

• autosomal dominant loss of lmx-1 
• effecs dorsal development
• show hypoplastic nails and lack of patella in knee
• evidence of ventralization in limb

TPTPs

• ZPA regulatory sequence (ZRS) regulates shh
• distinctly weird fingers associated with minor disruptions of this 

Hand-Foot-Genital Syndrome

• autosomal dominant linked to HoxA13
• HoxA13 important for establishing proximal-distal growth
• limb malformations and urogenital defects
• bilateral thumb and great toe defects from shortening of distal phlanx and first metacarpel/tarsal
• delayed ossification of wrist
• short middle phalanges of 5th digit

Polydactylyl

• addition of digit(1 in 500 births)
• extra digit usually bilateral, underformed and lack muscle development
• teratogen or autosomal dominant
• preaxial thumb side, post-axial 5th digit side

Syndactylyl

• fusion of fingers (1 in 2000)
• autosomal dominant/recessive
• best guess is Hox gene involvement
• cutaneous(webbing) or osseous(rays/bone)
• most common between 3 and 4 digit