26 - Limb Development Flashcards
What are the basic components of the adult limb?
Skeletal elements, skeletal muscles, fibrous connective tissue separating the compartments, neurovascular structures, and skin.
The limbs have proximal, intermediate, and distal segments.
What are the limb precursor tissues?
Limb Mesenchyme: somatic mesoderm
Surface Ectoderm (surrounds somatic mesoderm)
What are the general characteristics of limb development?
It’s a multi-step manner, steps blend into one another to form a continuum of development.
Appearance, patterning, and differentiation occur simultaneously but in subsequent segments.
Upper limb is ahead of lower limb by about 1-2 days.
What is step 1 of limb development?
Establishment of limb field:
- bilateral areas of somatic mesoderm
- Induced by gene expression
What is step 2 of limb development? What structure forms?
Budding (appearance): upper limb on says 26/27, lower on 28/29
- located at specific axial levels
- Inherent property of mesoderm
Apical Ectodermal Ridge (AER): ectodermal thickening at the dorsal/ventral surface interface. This is important for signaling.
What is the third step in limb development during weeks 5-9? What is this a result of?
Elongation of the limb: segments appear along a proximal-distal axis.
- Results from epithelial-mesenchyme interactions at AER/mesoderm interface.
What is the 4th step of limb development?
Tissue formation and organization (begins at week 5)
- Differentiation occurs in the proximal-distal direction
- Somatic mesoderm condenses to form cartilage that’s eventually replaced by bone.
- Somite derived from myoblast migrate into limb to form skeletal muscles
- Nerves and vascular precursors migrate into limb
Limb development occurs simultaneously along what three axes?
- Proximal-Distal: elongation, segment formation
- Anterior-Posterior: cranial-audal/preaxial-postaxial borders; digit development
- Dorsal-Ventral: compartments - muscles and neurovascular structures
Describe the interaction between the AER and the mesencyme during limb development?
Mesenchyme: induces AER (Fgf10), sustains AER, and determines limb type (upper or lower)
AER: maintains prolif. pool of mesenchyme cells for linear growth (Fgf8), paintains A-P axis signaling center (ZPA), and interacts with P-D and A-P specific proteins to provide mesenchyme cells with positional information.
What signaling molecules are released by the prosimal limb? What about the distal limb?
Proximal: retinoic acid
Distal: Fgf and Wnt
What is the fate of the mesenchyme adjacent to the AER in the limb bud?
It forms segment-specific skeletal elements and fibrous CT.
What happens if the AER is removed? What about if it’s duplicated?
Limb truncation: amelia (lack of limb) or micromelia (partial limb development).
Duplication of AER causes segment duplication.
How common are limb malformations?
Affect 2/1000 births.
Can be mild-severe.
What results from a transverse failure of formation of parts?
Amputation along the proximal-distal axis.
What develops along the anterior-posterior axis?
The digits.
Preaxial and postaxial borders form along this axis; thumb and big toe are preaxial.
What signaling center (other than AER) controls anterior-posterior patterning? What are the mediators involved in anterior-posterior patterning?
Zone of Polarizing Activity (ZPA) - located along the posterior border of the limb.
- Sonic hedge hog (Shh)
- Retinoic acid has same effect
____ gene combinatorial expression controls digit formation.
Hox gene.
An additional ZPA like signal (Shh, Retinoic acid) can set up a secondary focus on Hox gene expression.
What can result from a longitudinal failure of formation of parts? What are some examples of what can occur?
Amputation along the anterior-posterior axis.
Along the preaxial or postaxial border, or median plane.
Absence of radius, oligodactyly of lobster.
What is this an image of?
Fibular hemimelia - missing fibula
What is the associated deformity and what could have caused it?
Phocomelia - means “seal-like”
Thalidomide can cause this.
What role does apoptosis play in development?
Separation of digits, absence of distal phalanx of large digit.
What can result from a failure of differentiation (of parts) during limb development?
Syndactyly: digits stuck together
Sirenomelia: mermaid looking caudal end with no feet or definite structures
Triphalangeal Thumb: three digits on your thumb
What influences development along the dorsal-ventral axis of the limb?
- Skeletal muscles: myoblasts organize into dorsal and ventral premuscle masses
- Neural and vascular structures
- Limb compartmentalizaton
What are the madiators of dorsal-ventral patterning?
Secreted factors like Wnt 7a and TF engrailed (En)
