Limb Development: An Illustration of Key Principles & Concepts

Question 1

Limb growth from bud

Induction of limb buds at specific axial levels

Cells respond to cell type specific ways to a limited repertoire of signals, activating specific transcription programmes (cells are already partially specified)

Activation of position specific…genes (activation of different … genes influences which structures form at different points along the limb

Tbx transcription factors -Tbx5expressedrostrallyandTbx4expressedcaudally

Hox genes also have a role in patterning

Limb bud is…..covered by….(which ultimately forms the epidermis)

Answer 1

hox
lateral plate mesoderm
ectoderm

Question 2

Outgrowth and patterning

…….. interactions control outgrowth

Proximo-distalpatterning -…….. - ……………

AER maintains a region ofdividing cellsproximalto it called theprogress zone. Signalling between the AER and progress zone is important for ………….

Removal of the AER ……………

Answer 2

Epithelial-mesenchymal
mesodermcause the overlyingectodermtothickenand from theapical ectodermal ridge(AER) - distal tip of limb bud
limb elongation
stunts skeletal development- The time at which the apical ridge is removed determines the level of truncation; when the ridge is removed early, only proximal structures (such as humerus) are formed, whereas when the ridge is removed later on, more of the limb develops and it is the tip of the limb that is missing.

Question 3

What controls Anteroposterior(rostral-caudal) patterning

Answer 3

Anteroposterior(rostral-caudal) patterning - patterned by a group of mesenchymal cells called thezone of polarising activity(ZPA) on the posterior side

SHH= initial signal

Transplantation of ZPA from a donor onto the anterior edge of the limb bud results in mirror image polydactyly

Question 4

Development of limb structures

Answer 4

Development of long bones

Mesenchymal core forms ahyaline cartilagemodel in the6th week

Endochondral ossificationoccurs around12thweek (see 5.2)

Epiphyseal plate organisation (see 5.2)

Question 5

Name Abnormalities of long bone growth

Answer 5

Dwarfism

FGF receptor 3 (FGFR3) is a binding site for GFs and is a negative regulator (stops growth)

Mouse KO of FGFR3 causes mice to have longer bones than control

Clinical relevance - Achondroplasia - mutation in FGFR3 so that it is stimulated without GF binding, accelerating inhibitory effects causing shorter ‘long bones’

Giantism
Overproduction of growth hormone - bones continue to grow

Question 6

Muscle formation

Answer 6

Migration ofhypaxial myotome(from somite) into limb to form muscles

Formsdorsalandventral condensationsthat give rise to the extensor (D) and flexor (V) muscles

Question 7

Segmental innervation of skin and muscles

Answer 7

Ventral branches of spinal nerves come together at the limb bud to form plexuses (brachial and lumbosacral) before entering limb separately makingdorsal(C5, C6, C7) andventral(C8, T1, T2) branches

Motorinnervatesfirstthen sensory

Innervate nearest unoccupied territory of muscle

Upper limb:C5-T2

Lower limb:L4-S3