Limb Development Flashcards
Limb primordia
- Mesoderm
A. Paraxial: somites -> muscles only
B. Lateral plate: somatic mesoderm -> mesenchyme-> cartilage -> bone, CT, blood vessels
Nerve primordia
- Ectoderm
A. Neural crest: afferent innervation and myelination
B. Neural tube: efferent innervation
*sympathetics and parasympathetics
AER (apical ectodermal ridge)
Ridge of ectoderm along cranial/caudal axis where limb buds form
ZPA (zone of polarizing activity)
Forms at caudal end of limb bud
1. Creates SHH gradient
FGF (fibroblast growth factors)
FGF10 -> AER secretes FGF8 -> ZPA
SHH (sonic hedgehog)
Primary growth factor
1. Gradient defines anterior/posterior limb pattern
BMP (bone morphogenic protein)
- Expressed by ventral ectoderm
- BMP -> EN1 to set up dorsal/ventral gradient
- Helps -> AER via FGF10
- Vital for finger differentiation
A. Apoptosis in webbing
HOX (homeobox domain genes)
- HOXa and HOXd = primary determinants of bone morphology
2. HOXD 9-13 expression based on A/P and P/D concentration gradients of SHH, FGFs, and WNT7a
WNT7a
Dorsal limb ectoderm
- Establishes dorsal/ventral gradient
- Interacts w/ AER-FGF -> SHH
- Maintain proximal/distal axis by maintaining mesenchyme along AER
EN1 (entrained 1)
Stimulated be BMP in ventral limb
1. Suppresses WNT7a ventrally => WNT7a dorsal/ventral gradient
Abnormal limb development
- Change in regulation of primary players -> cascade effect
- Environmental factors: teratogens during let dev. Periods
A. Alcohol
B. Thalidomide
Axes of growth
- Ant/post -> lat/medial
- Prox/distal
- Dorsal/ventral -> post/ant
* starts ant/post like quadruped
Anterior/posterior gradient formation
3 weeks
1. Growth initiates as bud forms
A. FGF10 from mesenchyme -> AER forms outgrowth in ectoderm
B. Cells of AER
1. Stimulate FGF8 -> distal growth
2. Stimulate ZPA form at post aspect-> ant/post gradient
C. ZPA releases SHH -> ant/post gradient
1. SHH gradient dictated bone formation
A. Thumb and radius- low/absent [SHH]
B. 2nd and 3rd digits - med [SHH]
C. 4th and 5th digits and ulna - high [SHH]
- Cross-sections
A. Zeugopod- arm (radius/ulna)
B. Autopod - hand
C. Stylopod- humerus
Amelia
Absence of limbs
1. Suppression of limb bud dev. During 4th week
A. No ZPA
Polydactyly
Extra fingers
1. Cause: error in SHH transcription w/in limb buds -> A/P gradient mutations
- Pre-axial: 2 thumbs
Bradydactyly
Short terminal phalanges
1. Cause: HOXD 9-13 mutation
Digit formation
- Phalanx forming region stim interdigital mesenchyme to differentiate according to pre/post axial gradient
- Based on SHH signaling
- Mediated by BMP
- Weeks 4-8
A. Limb buds
B. Paddle-shaped hand and footplates
C. Digital rays
D. Notched between digital rays
E. Webbed fingers/toes
F. Separate digits
Syndactyly
Webbing 1. Incomplete formation of interdigital clefts 2. Cause: lack apoptosis between digits A. Usually BMP mutations B. Can involve SHH mutation
Proximal/distal gradient
- Differentiation front model
A. PZ (proliferating zone) - undifferentiated front along AER
B. AER produces FGF8 -> mesenchymal cell division in PZ
C. PZ differentiates according to distal distance traveled
D. PZ position relative to AER determines HOXD gene expression => prox/distal tissue density
E. HOXD9-13 control tissue ID beyond differentiation front
Meromelia
Partial absence of limbs
1. Terminal: missing hands
2. Intercalary: missing parts
A. Phocomelia: hands present, prox parts missing
B. Hemimelia: missing at least one zeugopod bone (radius/ulna)
3. Cause: disruption of prox/distal dev. In 5th week
A. Variable mutations
B. Mostly HOXD mutations
Dorsal/ventral gradient
As limb bud elongates
- WNT7a in dorsal ectoderm
- EN1 in ventral ectoderm
- EN1 inhibits WNT7a ventrally => WNT7a dorsal/ventral gradient
- Mesenchyme differentiates ant/post limb compartments
Limb rotation
7-8 weeks 1. Upper limb rotates 90 degrees laterally -> A. Elbow point post B. All extensors post C. All flexors ant 2. Lower limb rotates 90 degrees medially-> A. Knee point ant B. Leg and foot flexors post C. Extensors ant
Bone development
- Not scleratomes of somites bc appendicular, not axial
- Endochondral ossification
A. Week 5: mesenchymal models made from lateral plate mesoderm
B. Week 6: mesenchymal tissue in hand plates condense -> cartilaginous digital rays
C. Week 7: start ossification long bones- Ossification centers in all long bones 12th week
- Carpals don’t ossify until after birth
Fusion of epiphyses
- Growth plates between epiphyses and diaphyses
- Happens at different time depending on location
- Most fuse by 18-20 y/o
Dwarfism
- Hypochondroplasia
- Achondroplasia
- Chondrodysplasia
- Cause: FGF3 mutation -> problems w/ collagen production or turning collagen to bone
- Epiphyses and diaphyses fuse early or fail to fuse
Muscle development
- Week 5: ventral rami invade limb buds carrying myoblasts from C5-T1 somites in upper limb
A. L2-S3 somites in lower limb - Myocytes aggregate and proliferate -> ventral/dorsal muscle mass
- Mesenchyme from lateral plate mesoderm -> ligaments and blood vessels
- Mytotomes: set of muscles innervation by specific spinal n.
A. Muscle mass from each myotome porliferated into limb prox -> distal
B. Overlap from migration/fusion of myotomes
Dermatome development
Sensory axons enter limb bud after motor axons from neural crest
1. Sensory nerves envelope in epidermis and pulled along ventral axis pre -> post axial
