Limb Development

Question 1

Appearance of limb buds

Answer 1

• by 4th week, paired upper/lower limb buds from ventrolateral body wall
• upper day 26-27, lower 1-2 days later

Question 2

Limb bud structure

Answer 2

• mesencymal core (from somatic layer of lateral plate mesoderm)
• covered by ectoderm
• activation of mesenchymal cells starts limb development

Question 3

Lateral plate mesoderm

Answer 3

• subdivision of intraembryonic (2º) mesoderm

- forms CT of limbs

Question 4

Intraembryonic mesoderm

Answer 4

• Lateral plate-CT of limbs
• Paraxial-somites
• Intermediate-UG system

Question 5

Derivatives of Somites

Answer 5

• sclerotome: vertebrae & ribs
• myotome: muscle
• Dertatome: Connective tissue (dermis)

Question 6

Activation of mesenchyme

Answer 6

• Induce formation of Apical ectodermal ridge

- mesenchyme condenses to form skeleton and CT

Question 7

AER

Answer 7

• apical ectodermal ridge
• ectodermal thickening at apex of each limb bud
• inductive effect on mesencyme: proliferation (progress zone); growth and develompemtn (proximodistal axis)

Question 8

Proximodistal axis

Answer 8

• signaling center: AER
• signaling molecule: Fibroblast growth factors (FGF) -2, -4, -8
• maintains progress zone

Question 9

Anteroposterior axis

Answer 9

• signaling center: Zone of Polarizing Activity (ZPA)(cell cluster at posterior border of limb near body wall)
• signal: Sonic Hedgehog (Shh, induced by Retinoic acid (vit A) from ZPA)
• correct order of digets (thumb to little finger, radial to medial)

Question 10

Dorsoventral Axis

Answer 10

• signaling center: dorsal and ventral ectoderms
• signal: Wnt-7a (dorsal), En-1 (ventral)
• En-1 inhibits Wnt-7a, restricting it to dorsal ectoderm maintaining orientation of palmar vs dorsal survaces

Question 11

What signals induce formation of limb buds of forelimbs?

Answer 11

TBX5, FGF-10 in lateral plate mesoderm C5-T1 (around somites 16-20)

Question 12

What signals induce formation of limb buds of hindlims?

Answer 12

TBX4, FGF-10 in lateral plate mesoderm L4-S3 (starting around somites 27 and ending caudal to that)

Question 13

Hand and foot plates form when?

Answer 13

5th week or 32 days

Question 14

Digital ray formation

Answer 14

6th week/42 days

-tissues b/w digital rays undergoes apoptosis to form notches

Question 15

digits are distinct @ …?

Answer 15

8th week/56 days

Question 16

@ week 7

Answer 16

• upper limbs bent at elbow

- fingers short and webbed

Question 17

Positional changes of developing limbs

Answer 17

• 48 days: limbs extend ventrally; hand and foot plates face each other
• 51 days: upper limbs bent @ elbows, hands curve over thorax
• 54 days: soles of feet face medially
• 56 days: elbows point caudally, knees point crainially (limb rotation)

Question 18

Limb rotation

Answer 18

90º
upper limb: laterally (flexors-ant, extensors-post, thumb lateral)
lower limb: medially (flexors-post, extensors-ant, big toe medial)

Question 19

Development of cartilagenous bones

Answer 19

• 5th week: chondrification centers
• 6th week: entire limb skeleton is cartilaginous
• 7th weeek: 1º ossification centers formed in long bones (osteogenesis) (includes phalanges, metacarpals, metatarsals)
• Carpal and Tarsal bones: ossification begins in 1st year after birth

Question 20

Ossification of Appendicular skeleton

Answer 20

• Endocondrial ossification (except clavicle)
• diaphysis @ week 7-8 (most 1º ossification centers form in appedicular skeleton by week 12)
• epiphysis during 1st 4 years
• epiphysseal plate b/w: growth plate, adds length, persists til growth is over (end of puberty)

Question 21

Rickets

Answer 21

Vitamin D deficeincy–>impaired Ca2+ absorption–>disturbance in soofication of epiphyseal plates (short and deformed limbs)

Question 22

Achondroplasia

Answer 22

• Autosomal dominant 1:15,000
• premature fusion of epiphyses
• short stature
• bowed limbs
• short trunk
• enlarged head

Question 23

Development of Myotomes (limbs)

Answer 23

2 divisions:

• Epaxial (dorsal)–>intrinsic muscles of back, dorsal rami
• Hypaxial (ventral)–>everything else (including limbs and abdomen), segmentation retained in some regions, ventral rami

-limbs: myogenic precursor cells migrate to limb bud and differentiate into myoblasts–>aggregate as muscle mass in limb bud as long bones develop–>separate into flexor and extensor compartments

Question 24

Development of Dermatomes

Answer 24

• motor axons arise from spinal cord and enter limb bud during 5th week
• sensory axons follow after (use motor axons for guidance)

-neural crest cells–>precursors of schwann cells–>surround motor and sensor nerve fibers in limbs–>form neurolemma and myelin sheaths

dermatome=area of skin supplied by single spinal nerve and spinal ganglion

spinal nerves in segmental bands and orderly distribution recognized even after growth of limbs

Question 25

Syndactyly

Answer 25

Cutaneous: webbing of digits (failure of loose mesenchyme b/w digital rays to undergo apoptosis) Osseous: fusion of bones (failure of notches to form) Upper limb--> usually 3rd and 4th digits Lower limb--> digits 2 and 3

Question 26

Polydactyly

Answer 26

- extra digits (supernumerary) - relatively common (1:1000 esp. Amish in USA) - Disruption fo anteroposterior pattern - severe type often has fusion of bones of digits

Question 27

Congenital club foot

Answer 27

- Tailpes equinovarus - Foot turned medially and inverted - common (1:1000) - usually associated with other defects (VACTERL)

Question 28

Amelia

Answer 28

- Complete absence of limbs - suppression of limb bud development in 4th week - can be caused by thalidomide (drug used to prevent morning sickness in '60s until link was made)

Question 29

Meromelia

Answer 29

- Partial absence of limbs (some limbs or parts of limbs) | - disturbane of limb development in 5th week

Question 30

Cleft hand and foot

Answer 30

- absence of 1 or more central digits - failure of development of ≥1 digitl ray - remaining digits are partially or completely fused - rare anomaly: lobster-claw deformity

Question 31

Amniotic Band syndrome

Answer 31

-tears in aminion result in amniotic bands -can encircle limbs and digits-->constriction and amputations -cause unknown (infection speculated) ~1:1200 births