From what part of the embryo do somites arise
Paraxial Mesoderm
From what part(s) of the embryo do limbs arise
Somites and Lateral Plate Mesoderm
Discuss the role of paraxial mesoderm in limb formation
Dermatome gives rise to dermis connective tissue
Mytotome gives rise to limb muscles
Discuss the role of lateral plate mesoderm in limb formation
Bones of upper & lower limbs
Blood Vessels
Connective tissue (except for that of the dermis) (e.g. Ligaments, Tendons, etc.)
Limb Bud
Very first limb precursor formed in an embryo
When do limb buds form in an embryo
Week 4
Early embryonic development progression of limbs
A - 5 Weeks
B - 6
C - 7
What is the main development in limbs after 8 weeks
The limb elements just increase in size
Lag between upper and lower limb
Lower limb development lags behind upper limb development by 1 to 2 days
How are limbs initially formed
Firstly as a cartilagenous model
Discuss the osteological development of Lower Limb growth from weeks 6 to 8
At first it is cartilage, with bones starting to fill in at 6 weeks
Then the bones lengthen and others continue to form
Finally by 8 weeks all the major bones have formed
Which bones/bone groups of the lower limb are formed at 6 weeks in an embryo
Pelvis, Thigh/Legs, Footplate cartilages
Which bones/bone groups of the lower limb are formed at 7 weeks in an embryo
Tarsal Cartilages
Which bones/bone groups of the lower limb are formed at 8 weeks in an embryo
Metatarsal Cartilages
Ischium
What are the toes like at 7 weeks
Still connected and not formed as individual structures
Rostral/Caudal
Rostral is the Axis situated towards the head embryologically
Caudal is the Axis situated towards the ‘tail’ embryologically
Relevant axes in the embryological development of a limb
Proximal - Distal
Anterior (Rostral) - Posterior (Caudal)
Dorsal - Ventral
What part of the embryo initiates limb outgrowth in the proximal-distal axis
The Apical Ectodermal Ridge at the tip of the limb buds
What direction of growth is the Apical Ectodermal Ridge (AER) responsible for
Proximo-distal growth
Effect of AER on mesenchyme
Causes proliferation of cartilage from mesenchyme
HOX Genes
Homeobox Genes
Group of related genes that specify regions of the body plan of an embryo
HOX Proteins encode & specify the characteristics of ‘position’
Depending on which HOX genes is expressed, difference elements will form
AER vs HOX Genes
HOX genes determines the specific components/bones that form while the AER is responsible for the lengthening/differentiation of the axis as a whole
Result of Disruption of HOX Genes
Loss of Specific Limb Elements
Potential causes of HOX Gene disruption
Mutation, Teratogens like retinoic acid/ethanol
What parts of the embryo initiates Dorso-Ventral Patterning of the limbs
WNT7 is expressed on the Dorsal Surface
ENGRAILED-1 and Bone Morphogenic Protein are expressed on the Ventral surface
Relation of Dorso-Ventral Patterning with Proximo-Distal Outgrowth; and relevance
Actors of Dorso-Ventral patterning are also responsible in some part of proximo-distal outgrowth as they help set up the AER
Disruptions in D-V signals can therefore also affect proximo-distal growth as well
What part of the embryo initiates Anterior-Posterior Limb Patterning
AP Patterning is initiated by the zone of polarising activity (ZPA)
It secretes an entity called sonic hedgehog which specifies the formation of posterior elements (Little Fingers)
There is a gradation of how much signalling there is across the limb from the ZPA
Results of loss/upregulation of ZPA
Results of loss of posterior elements (e.g. little finger/toe)
Upregulation results in additional posterior elements (e.g. polydactyly on hypothenar side)
Results of duplication of ZPA
Duplication of Posterior elements/disrupted pattern
Effect of ZPA on AER maintenance
Disruption of ZPA often results in limb growth dysregulation due to its effects on AER
- ZPA Upregulation causes a limb to be too long
- ZPA Down-regulation causes a limb to be too short
Order of finger formation - Result of disruption of AP Patterning
Posterior elements (Little finger/Ulna) are formed before anterior elements (due to spread of ZPA)
Disruption of AP patterning and growth can also lead to loss of anterior elements (e.g. loss of thumb and/or radius)
FGF
Signal arising from AER causing condensation of cartilage and limb lengthening
Sonic Hedgehog
Signal Released by ZPA determining AP ais
WNT & Engrailed
Signals working to define Dorsoventral axis of limbs
Why are limb defects usually so complex
The different Mediators of limb growth act on each other causing complex deformities involving multiple axes
What process occurs to separate the digits in the hand/foot
Apoptosis to remove the tissue between cartilagenous blocks
Which signalling proteins/areas are involved in digit apoptosis
It is dependent on BMP with influence from Sonic Hedgehog and ZPA
What is the consequence of a disruption in digit apoptosis and what is its most common presentation
Syndactyly (Fingers remain attached to each other), most commonly digits 3, 4 & 5
Development of limb bones
This occurs through endochondral ossification as mesenchyme begins to form chondrocytes which then lay down a ‘model’ of the bone in cartilage
Like most long bones, the shaft (Diaphysis) forms quite quickly (and is hollow) while the ends (Epiphysis) remain cartilagenous with an epiphyseal growth plate
A blood vessel supplies diaphysis first then later goes into the epiphysis forming a secondary ossification centre
***Phalanges only have one ossification centre
What signalling causes endochondral ossification and what external factor disrupts this process
FGF Signalling causing chondrocyte proliferation & growth plate maintenance
Steroid hormones switch this off
Types of Paraxial Mesoderm and what they develop into
- Sclerotome which develops into vertberal and rib bones
- Myotome which develops into muscle
- Dermatome which develops into dermal connective tissue
**C5-T1 Myotomes provide muscles for upper limb
Divisions of Myotome
Primaxial Myotome
Abaxial Myotome
Primaxial Myotome
Adjacent to neural tube - affected by signalling factors of neural tube to generate muscle precursors with limited migratory potential
**Muscles nearer to spine
Abaxial Myotome
Ventrolateral Myoblasts - Responds to signals from adjacent lateral plate mesoderm & ectoderm to give rise to a migratory population
**Gives rise to limb muscles among others
Divisions of Primaxial Myotome
Epaxial Muscles (Epimere) of the back (Innervated by dorsal rami)
Hypaxial Muscles (Hypomere) of the body wall [prevertebrals, intercostals, "strap muscles", scalenes, geniohyoid, proximal limb girdle (rhomboids, levator scapulae,, latissimus dorsi)] (Innervated by ventral rami)
Myotomes that form the upper and lower limb
Upper: C5-T1
Lower: L2-S2
Discuss the rotation of the limbs
The limb buds lengthen and take their nerve supply with them
The distal limbs then start to flatten into a paddle with the great toe & thumb most anterior
By Week 7 limbs undergo torsion in opposite directions so the elbow is caudal and knee is cranial
As we continue, the upper limb simply lengthens while the lower limb undergoes torsion so that the foot faces downwards - the great toe which was initially anterior is now medial
Discuss/Be aware of the dermatome orientation in the upper limb
Why is the pattern of lower limb dermatomes distorted
The torsion that occurs in the lower limb
Achondroplastic Dwarfism
Bone growth disorder - disproportionate dwarfism with short statute, normal sized torso and short limbs
Occurs in defects in chondrocyte proliferation causing premature closure of epiphyseal growth plates - probably FGF Signalling
Usually a new mutation but can be passed down heterozygously (Dominant)
Homozygotes tend not to survive
Spondyloepiphyseal Dysplasia Congenita (SED/SDC)
Rare bone growth disorder resulting in dwarfism with characteristic skeletal abnormalities affecting bones of spine and ends of bones
Often also problems with vision/hearing
**Subtype of collagen disease affecting types II & XI (DONT NEED TO KNOW I THINK)
Polydactyly
Too many fingers - congenital abnormality
Syndactyly
Webbing of two or more fingers together - congenital abnormality
The disruption of what causes most limb growth defects
Loss of FGF Signalling
Amelia
Absence of entire limb
Meromelia
Absence of part of a limb
Phocomelia
Short/poorly formed limb
Adactyly
Absence of digits
Ectrodactyly
“Lobster-Claw” deformity - variant of adactyly where middle digit is lost
What causes polydactyly
Usually upregulation of Sonic Hedgehog pathway
What causes syndactyly
BMP or Sonic Hedgehog disruption
