Limb Development

Question 1

When do limb buds form

Answer 1

week 4

Question 2

when do digits separate

Answer 2

week 8

Question 3

when does primary ossification occur

Answer 3

week 12

Question 4

What 3 things doppelgänger’s limbs develop from

Answer 4

1) somite (paraxial) mesoderm: muscles
2) Somatic (lateral plate) mesoderm: cartilage and bone
3) somatic (lateral plate) mesoderm: connective tissue

Collectively they are limb-forming mesoderm

Question 5

Explain limb formation starting with what Limb-Forming mesoderm releases

Answer 5

1) Limb-forming meso term releases FGF-10, which induces the AER (apical ectodermal ridge) to release FGF-4 and FGF-8
2) FGF-4 and FGF-8 stimulate the limb-forming mesoderm to proliferate, causing growth in the proximal to distal direction

Question 6

Where do limb buds appear?

Answer 6

Under the AER

Question 7

When do individual bone structure begin to differentiate

Answer 7

during proliferation of the limb-forming mesoderm

Question 8

What do the stylopod, zeugopod and autopod form

Answer 8

1) stylopod - humerus and femur
2) zeugopod - radius/ulna, fibia/tibia
3) autopod - carpals, metacarpals, digits, tarsal, metatarsals, digits

Question 9

When do upper limb and lower limb buds appear?

Answer 9

upper limb - 24 days

lower limb - 1-2days later

Question 10

What occurs during Week 4

Answer 10

Limb buds form

Question 11

What occurs during Week 5

Answer 11

• Hand and foot plates form
• chondrofication (cartilage) centers appear
• Limbs are LATERALLY & CAUDALLY facing

Question 12

What occurs during Week 6

Answer 12

Digital rays of hand form (somatic lat. plate mesoderm. condensing into digit shape)

Entire limb is CARTILAGINOUS

Libs BEND ANTERIORLY

Question 13

What occurs during Week 7

Answer 13

Digital rays of feet form (somatic lat. plate mesoderm. condensing into toe-like shape)

Osteogenesis of long bones

Upper limbs – rotate laterally 90degrees

Lower limbs – rotate Medially 90degrees

Question 14

What occurs during Week 8

Answer 14

Separate digits form due to APOPTOSIS of extra tissue which is stimulated by BMP

Lower limbs – “Barber pole” dermatome formation occurs

Question 15

Limb musculature is derived from ___ and occurs during ___

Answer 15

dorsolateral cells of the somite

week 5

Question 16

Explain how blood supply forms in the Upper limbs

Answer 16

Dorsal Aorta —> Intersegmental A. (enter limb bud) —> Primary Axial Artery —> Brachial A. ——(REMODLING OF ARTERIES TO CREATE ANATOMICAL VARIATION)—–> the limbs we’re born with

Question 17

Explain how blood supply forms in the lower limbs

Answer 17

Aorta —-> Intersegmental A. (enter limb bud) —–> Primary Axial A. —–> Deep Artery of the Thigh —-(REMODLING)—–> Leg Arteries

Question 18

Talipes Equinovarus

Answer 18

aka Club Foot

• Most common MSK defect
• 2x more in males
• sole of foot turned medially and is inverted
• ALL structure present, cases can be treated with casting

Question 19

Developmental Hip Dysplasia

Answer 19

• more common in women
• underdevelopment of the acetabulum, dislocation of femur from hip joint
• Clinical = joint laxity

Question 20

Proximo-distal Limb Patterning

Answer 20

Mesenchyme releases FGF-10, AER is stimulated to release FGF-4 and FGF-8 (continues in a cycle)

Question 21

What do Hox genes do?

Answer 21

Regulate types, shapes and positioning of bones

Tuning them off/on at specific times is what dictates shape/type/position

Question 22

Dorso-ventral patterning

Answer 22

Ventral Surface (Flexor muscles) = BMPS 
Dorsal surface (Extensor muscles) = Wnt7

Question 23

Anterior-Posterior Patterning

Answer 23

• Established by the Zone of Polarizing Activity (an area of mesenchyme that directs ant/post axis)
• ZPA releases SHH and Retinoic Acid which signals the posterior elements

Posterior first —-> Anterior follows after

Question 24

Clinically, why is it important that posterior elements from before anterior elements

Answer 24

Defects in posterior elements (little finger/ulna) formation and disruption of A-P patterning and growth can result in problems/loss of anterior elements (thumb/radius)

Question 25

What happens if there is a:

1) Loss of ZPA
2) Upregulation of ZPA
3) Duplication of ZPA

Answer 25

1) loss of posterior elements (digit or ulna)
2) Additional posterior elements (Polydactyly - extra digit)
3) duplication of posterior elements (little fingers on both sides of thumb

Question 26

Explain the following clinical limb development issues:

1) Polydactyly
2) Syndactyly
3) Bradydactyly
4) Meromelia
5) Phocomelia
6) Amelia
7) Arthrogryposis
8) Ectodactyly

Answer 26

1) extra digit, upreg of ZPA (Week 6 and 7 for hands and feet respectively)
2) Fusion of digits – failure of BMP to apoptosis the tissue
3) Short digits —- failure of BMP to to apoptosis tissue
4) Part of limb is absent (during week 4)
5) Type of Meromelia where the hands and feet are close to the body -issues with FGF signaling during WEEK 4
6) No limb bud formed — THALIDOMIDE
7) Congenital joint contractures – neurological defects, joint/contiguous tissue problems
8) Split Foot/Hand (looks like a claw) —- Center of aER did not develop properly (WEEK 6 for hand……WEEK 7 for foot