Limbs

Question 1

What weeks does human limb development take place?

Answer 1

4-8

Question 2

Which limb begins to develop first, how much before?

Answer 2

Upper limb couple days before lower limb

Question 3

What drives proximal distal limb patterning?

Answer 3

Limb grows progressively, digits forming last

Progress zone model: cells spend shorter time in the zone form more proximal structures than those staying longer

Question 4

What drives anterior posterior/craniocaudal (i.e. thumb to little finger) patterning of limb?

Answer 4

Patterned by signals from ZPA (mesenchymal cells at posterior limb margin - zone of polarising activity).

Cells closest to it form posterior structures.

Question 5

What forms dorsal/ventral patterning of limb (i.e. back or palm of hand)?

Answer 5

Pattern controlled by non ridge ectoderm,

Question 6

How does the limb formation begin?

Answer 6

Mesenchymal cells from the lateral plate mesoderm proliferate to the point that they cause the ectoderm above to bulge out, forming a limb bud

Question 7

What mesoderm contributes to the limbs?

Answer 7

Lateral plate mesoderm

Question 8

What creates the progress zone that drives proximal distal limb patterning?

Answer 8

The apical ectodermal ridge (AER) creates and maintains a zone of cell proliferation known as the progress zone

Question 9

What is the AER?

Answer 9

An organizer at the end of the limb bud, called the apical ectodermal ridge (AER). Drives cell proliferation.

Question 10

What patterns the digits?

Answer 10

Gradient of Shh, highest in 5th digit, lowest in 1st

Question 11

What creates the Shh gradient for generating craniocaudal patterning?

Answer 11

ZPA

Question 12

What digit forms on the side of the ZPA?

Answer 12

5th

Question 13

When do hyaline cartilage models of the bone form?

Answer 13

Start in 6th week, full set by end of 6th week

Question 14

By what week are there primary ossification centres in all bones?

Answer 14

12

Question 15

Is limb identity specified before they grow out (i.e. upper limb vs lower limb)?

Answer 15

Yes

Question 16

What does early limb bud consist of?

Answer 16

Lateral plate mesoderm - skeletal elements covered by ectoderm (cuboidal epithelium)

Question 17

What drives limb bud outgrowth?

Answer 17

Reciprocal epithelial mesenchymal interactions between these cells governs limb initiation and outgrowth.

Question 18

What happens to overlying ectoderm as limb buds out?

Answer 18

Thickens and forms apical ectodermal ridge AER (which edges distal tip of bud)

Question 19

What signalling allows bud outgrowth?

Answer 19

Signalling between AER and progress zone

AER induces growth of underlying mesenchyme so mesodermal growth causes limb bud to grow

Also mesenchyme signals back to AER

Question 20

How does bone grow in limb?

Answer 20

Endochondral ossification

Question 21

What are mesenchymal stem cells precursor for?

Answer 21

Chondrocytes

Question 22

What are skeletal elements of limbs derived from?

Answer 22

Lateral plate mesoderm

Question 23

What are skin and associated structures derived from?

Answer 23

Ectoderm

Question 24

What are blood vessels derived from in limbs?

Answer 24

Angioblasts in mesoderm

Question 25

Describe endochondral ossification

Answer 25

Chondrocytes form cartilage model

Chondroblasts in diaphysis undergo hypertrophy and apoptosis as they mineralise surrounding matrix, chondrocytes die - create cavities

Blood vessels invade - brings osteoblasts/osteoclasts

Osteoblasts and osteoclasts modify the calcified cartilage matrix into spongy bone - at birth diaphysis ossified

Dense, irregular connective tissue forms a sheath (periosteum) around the bones.

Epiphysial plate contains proliferating chondrocytes and continues to grow

Question 26

What part of the bone continues to grow after birth?

Answer 26

Epiphysial plate (hyaline cartilage persists here)

Question 27

What do muscles arise from?

Answer 27

Somatic mesoderm (myotome) which invades into limb

Dorsal/ventral muscle masses - dorsal extensor, ventral flexor muscles

Question 28

How do nerves come together in limb development?

Answer 28

Ventral branches of spinal nerve (C5-T1) and (L4-S3) innervate limb muscles

Come together and form plexus at limb bud base before separated into dorsal and ventral branches and entering limb

Question 29

What branches of spinal nerves innervate limb muscles?

Answer 29

(C5-T1) and (L2-S3)

Question 30

Where do sensory neurones follow into limbs?

Answer 30

Follow motor neurones

Question 31

Do motor nerves follow sensory nerves?

Answer 31

No, sensory nerves follow motor nerves

Question 32

What sculpts axilla and separation of digits?

Answer 32

Apoptosis

Question 33

Describe rotation of the limbs in development and what’s the effect?

Answer 33

Medial rotation of lower limb

Less pronouned lateral rotation of upper limb around long axis

Spiralling dermatomes

Question 34

What happens to dermatomes as limb extends?

Answer 34

Ectoderm from body wall recruited as limb extends -pulls in dermatome regions from other dermatomes

Question 35

What happens in achondroplasia?

Answer 35

Mutation in FGFR3 receptor gene

Constitutively active and cartilage doesn’t develop into bone and individual is shorter

Question 36

What happens in gigantism?

Answer 36

GF and IGF1 are potentially in excess

Increased levels of growth hormone before the fusion of the growth plate which usually occurs at some point soon after puberty.