Development of the Limbs

Question 1

What is the role of HOX genes?

Answer 1

Homologous to those found in Drosophila - They are involved in programming what cell does what, control the Complex interplay of gene activation and transcription, and signalling via many proteins and growth factors

Question 2

What week does the limb out-pouching occur?

Answer 2

5 weeks

Question 3

What week does the limb look like the upper limb with spade like hands occur?

Answer 3

6 weeks

Question 4

What week does the arm fully form (not muscles fully)?

Answer 4

8 weeks

Question 5

What is the mesoderm? What does it form?

Answer 5

Mesoderm populates the gap between the endoderm and ectoderm it becomes a uniform layer then starts to differentiate. Mesoderm gives rise to muscles, BV’s, Ct and bone.

Question 6

What are the three parts the mesoderm differentiates into?

Answer 6

Somite, intermediate and lateral plate.

Question 7

What does the lateral plate mesoderm form?

Answer 7

limb bones and connective tissues

Question 8

What does the somite mesoderm form?

Answer 8

limb muscles

Question 9

What three layers does the lateral plate split into?

Answer 9

somatic, coelom and splanchnic

Question 10

What are the divisions of the somites?

Answer 10

ventral part - the sclerotome > vertebral column
dorsolateral part – the dermomyotome - which divides into a dermatome > dermis of the skin and a myotome > skeletal muscles

Question 11

What are the back muscles innervated by?

Answer 11

The back muscles - innervated by the dorsal rami of spinal nerves

Question 12

What are the thoracic and abdominal wall muscles muscles innervated by?

Answer 12

The thoracic and abdominal wall muscles and muscles of limbs - innervated by the ventral rami of spinal nerves

Question 13

Where do limb buds out-pouch from?

Answer 13

Outpouchings from the ventrolateral body wall

Question 14

What doe the limb buds initially consist of? where is this derived from?

Answer 14

Initially the buds consist of a core of tissue derived from lateral plate mesodermThis is covered by a layer of ectodermThe mesoderm core differentiates to form the bones and connective tissue of the limbs

Question 15

The mesoderm that will form the limb muscles migrates into the limb buds and divides into 2 parts. What are they?

Answer 15

Ventral part of the myotome: Gives flexor muscles of the UL and extensor muscles of UL
Dorsal part of the myotome: Dorsal rams and muscles of the back.

Question 16

What are the UL buds innervated by ?

Answer 16

branches of the ventral primary rami of spinal nerves C5-T1 (brachial plexus)

Question 17

What are the LL buds innervated by ?

Answer 17

The LL buds – ventral primary rami of spinal nerves L1-S3 (lumbosacral plexus)

Question 18

What does the dental part of the myotome further divide into? What do they give rise to?

Answer 18

Posterior condensation: Extensors and supinators of the UL and Extensors and abductors of the LL
Anterior condensation: Flexors and pronators of the UL and Flexors and adductors of the LL

Question 19

LIMB rotation draw out the dermatomes

Answer 19

C3 going all the way round to T4

Question 20

What are the three types of patterning?

Answer 20

Proximodistal, Craniocaudal and Dorsoventral

Question 21

What is Proximodistal Patterning?

Answer 21

Proximodistal – from the shoulder to the hand (and from the hip to the foot)

Question 22

What is Craniocaudal Patterning?

Answer 22

Craniocaudal – the thumb is most cranial digit and the little finger is most caudal

Question 23

What is Dorsoventral Patterning?

Answer 23

Dorsoventral – the palm of the hand and sole of the foot are ventral and the knuckle side of the hand and foot are dorsal

Question 24

How does Proximodistal outgrowth occur?

Answer 24

Mesenchymal core of the limb bud secretes a fibroblast growth factor (FGF 10).
This induces thickening of the overlying ectoderm along the tip of the limb bud – apical ectodermal ridge (AER)
The AER also expresses fibroblastic growth factors - FGF 4 and 8.
These cause rapid proliferation of mesenchymal cells underlying the AER – the progress zone.
The progress zone maintains proximodistal outgrowth of the limb

Question 25

What is the role of the apical ectodermal ridge?

Answer 25

The AER also expresses fibroblastic growth factors - FGF 4 and 8. These cause rapid proliferation of mesenchymal cells underlying the AER – the progress zone. The progress zone maintains proximodistal outgrowth of the limb.

Question 26

What is Meromelia?

Answer 26

Partial absence of a limb. There is later or partial loss of FGF signalling / AER disruption, hence arrest of proximodistal outgrowth. Vascular abnormalities may also be responsible

Question 27

What is Amelia?

Answer 27

Complete absence of a limb. Very early failure of FGF signalling / the AER. The progress zone does not develop and there is no proximodistal outgrowth

Question 28

What is Cleft hand / foot?

Answer 28

Failure of central part of the AER to form properly

Question 29

What does Ectopic FGF result in?

Answer 29

Supernumerary limbs

Question 30

How does Craniocaudal patterning occur?

Answer 30

Determined by a small region of mesenchyme in the caudal part of the limb bud – the zone of polarising activity (ZPA) - where sonic hedgehog (SHH) is expressed. SHH diffuses from the ZPA in a cranial direction. A high concentration of SHH induces caudal structures e.g. little finger Low concentrations induce cranial structures e.g. thumb.

Question 31

What does SHH cause?

Answer 31

SHH diffuses from the ZPA in a cranial direction. A high concentration of SHH induces caudal structures e.g. little finger Low concentrations induce cranial structures e.g. thumb.

Question 32

What causes Polydactyly?

Answer 32

Polydactyly, Extra digits, There can be duplication of structures in a mirror image fashion. Inappropriate/ectopic ZPA/ SHH expression involved

Question 33

How does Dorsoventral patterning occur?

Answer 33

Dorsal ectoderm expresses Wnt7 > Wnt7 induces activation of another gene, LMX1 > LMX1 essential for specifying the development of cells that become dorsal structures Ventral ectoderm expresses Engrailed-1 which inhibits Wnt7 so dorsal structures cannot develop

Question 34

What is Nail Patella syndrome?

Answer 34

A rare syndrome that affects the nails, bones, kidneys and eyes. The defect is in the LMX1B gene Abnormalities of the nails Some patients have absent or small, irregular patellae.

Question 35

When do digits form? How do the form?

Answer 35

Week 6 – terminal portion of limb buds flatten to form hand and foot plates. Programmed cell death - apoptosis - in the AER splits it into 5 parts which continue to grow to form fingers. Apoptosis continues between the digits.

Question 36

What is Syndactyly?

Answer 36

Fused digits | Failure of normal apoptosis

Question 37

Name some causes of limb abnormalities?

Answer 37

Genetics – hereditary or spontaneous mutations, Drugs – ‘teratogens’ – examples?, Environmental poisons, Maternal illness, Amniotic band syndrome, Unknown / unidentifiable causes in many cases

Question 38

What is Phocomelia?

Answer 38

Very rare, Digits develop prematurely.Proximal elements of limb absent, Can be due to genetic factors or teratogens – most commonly associated with thalidomide use (which inhibits the expression of FGF 10 and 8 and is thought to inhibit angiogenesis) Phocomelia is most commonly associated with thalidomide use. Thalidomide inhibits the expression of FGF 10 and 8 and is thought to inhibit angiogenesis This drug is still in use for certain conditions but tight controls are difficult to achieve in some developing countries