How does Limb Development Begin?
Begins with the activation of mesenchyme within the somatic layer of lateral mesoderm.
This somatic mesoderm forms the limb skeleton
Somites form the limb musculature
What are Limb Buds and when do they appear?
Small prominences that appear on the ventro-lateral body wall and extend ventrally at first.
Appear towards the end of Week 4 and lower limb development lags ~2 days behind upper limb.
What do Limb Buds consist of and how do they elongate?
Core of mesenchyme (flexible mesoderm) with a thin ectoderm (mostly square and some columnar epithelia) covering, except at the apex where the ectoderm is thickened - AER.
Elongation of the limb is through proliferation of mesenchyme core - rapid cell division and the cells are all interchangeable.
What are the different axes of the limb present?
Antero-posterior axis: from 1st digit to 5th I.e. thumb to little finger in Upper Limb
Dorsal: back of the hand and top of the foot
Ventral: palm of the hand and sole of the foot
Proximal-distal axis: base of the limb to the tips of the digits.
What is the major difference in the axis between embryo and adult?
In the embryo, the head is Anterior but in the adult, it is Superior
Similarly what is posterior to the embryo (towards the tail) becomes Inferior in adult
Embryo Ventral = Adult Anterior
Embryo Dorsal = Adult Posterior
What does the notochord become?
Remnant of the notochord becomes marooned by axial skeleton formation - becomes part of the intervertebral discs ('nucleus pulposus')
What is the AER?
Apical Ectodermal Ridge
Critical for limb bud outgrowth.
Orchestrates limb development proximal to distal axis.
Final stage is appearance of paddles (beginning of the reorganisation needed to form the digits) Then AER regresses.
How does the AER generate Proximal-Distal Axis Generation?
The AER exerts an inductive influence on the immediately underlying mesenchyme so the mesenchyme multiplies but remains undifferentiated - signalling molecules promote growth and development of the limbs (elongation).
But signalling molecules are diffusion- limited so proximal mesenchyme begins to differentiate into constituent tissues (the skeletal components of the axial skeleton) as it is too far away from the AER to receive the signals to stay undifferentiated.
Finally the AER induces development of the digits within the hand/foot plates before regressing,
What is the ZPA?
Zone of Polarising Activity
Signalling centre located at the posterior base of the limb bud.
Responsible for generation of asymmetry in the limbs - the anterior-posterior axis determination
Controls both patterning (generates mirror image of the limb) and maintains the AER.
What is Dorsoventral Patterning?
The AER marks the boundary between dorsal and ventral ectoderm.
Ectoderm exerts dorsalising and ventralising influences (via signalling molecules) over mesenchyme core. T
his initiates a signalling pattern within the ectoderm itself.
Briefly list the control of axial specification
Anterior-Posterior : ZPA - side to side (left and right hands always mirror images of each other)
Proximal-Distal: AER e.g. Shoulder to fingertips
Dorsal-Ventral: Ectoderm - front and back
Explain about Digital Rays in the Hand and Foot Plates
Mesenchyme condensations within plates form cartilaginous models of the digital bones.
Apoptosis of the tissue between the digits follows - sculpting of interdigital spaces
AER breaks up and is maintained only over the tips of the digital rays.
Explain the formation of bones
Signals from the AER to remain undifferentiated stop.
Lateral plate mesoderm condenses and differentiates
Cartilage model reforms Endochondral ossification
Secondary Ossification centres appear in the epiphyses; bone growth is maintained by cartilage forming regions.
- epiphyseal plates remain open and allow long bones to open and lengthen during childhood and adolescence.
Describe Musculature formation
Myogenic precursors migrate into limbs from somites and coalesce into 2 common muscle masses behind the newly formed skeletal elements (which have formed in the centre of the limb bud)
The precursors bring their innervations supply with them (spinal nerve innervates somite and all of its derivatives)
Individual muscles then split from common masses.
Describe the Rotation of the Limbs
Limbs extend ventrally at first but they rotate as they elongate.
Upper limb rotates laterally (thumb lateral)
Lower limb rotates medially (big tie is medial)
The upper and lower limbs rotate in different directions and to different degrees. Thus
Before rotation: thumbs up, elbows out, soles facing in, knees out
After rotation: thumbs out, elbows down, soles down, knees up
Hence in U/Limb, flexor compartment is anterior whilst in L/Limb, flexor compartment is posterior and vice versa,
Describe Limb Innervation
Upper limb bud appears opposite the caudal cervical spinal segments.
Lower limb appears opposite the lumbar and sacral spinal segments.
Spinal segments enter the limb bud early in its development. Without innervation development stalls.
Explain the Brachial Plexus
Muscles are compartmentalised and nerves grow into common muscle masses.
All Anterior divisions for anterior (ventral) compartment regroup to form medial and lateral cords therefore flexors are supplied by medial and lateral cord branches.
All Posterior divisions for posterior (dorsal) compartment regroup to form posterior cord, therefore extensors are supplied by posterior cord.
Define Dermatome and Myotome
Dermatome: strip of skin supplied by a single spinal nerve
Myotome: muscle/group of muscles supplied by a single spinal nerve
Can be examined clinically
Explain about Limb defects
Upper limb affected more often than lower limb (lag period of two days means they have different critical periods)
Occurrence - not very common (6/10000 live births)
Rare and usually hereditary but teratogen (interrupts development) induced defects have been described
Define the Common Limb Defects: Amelia, Meromelia, Phocomelia, Syndactyly, Polydactyly
Amelia: complete absence of a limb
Meromelia: partial absence of one or more limb structures e.g. Phocomelia (thalidomide is toxic to AER, prevent elongation of limb bud - severity of defect depends on timing of exposure to the drug)
Syndactyly: fusion if digits due to lack of apoptosis between digits - may involve just connective tissue or bones may be fused
Polydactyly: extra digits, genetic recessive trait - extra digit is incompletely formed and lacks proper muscle fixation.
Describe skeleton formation and further growth of the long bones
The mesenchymal skeleton is formed by cell aggregation to the limb.
To begin with the entire limb skeleton is cartilaginous.
Ossification of the long bones begins by the appearance of primary centres of ossification in the middle of the long bone.
Secondary ossification centres appear in the Epiphyses.
Bone growth is maintained by cartilage-forming epiphyseal growth plates.
Define preaxial, postaxial and name their borders
Preaxial -->thumb and big toe
Postaxial --> little finger and toe
Preaxial border is cranial
Postaxial border is caudal.
Explain about Syndactyly