Limb Development Flashcards
When does the limb start to develop?
around 4-8 weeks
-4 weeks: limb bud
Which limb develops first?
- fore limb
- hind limb 1 to 2 days later
Limb development is an interaction between what?
Epithelial-Mesenchymal interaction:
- Ectoderm
- Mesoderm
What do limbs arise from?
Lateral Plate Mesoderm
Where does the limb know where to start development on the embryo?
- competent stripe
- HOX genes are expressed along the competent stripe at the point where limbs develop
What initiates and maintains bud outgrowth?
- by establishing a positive feedback loop of FGF signaling comprised of FGF10 expressed in the Lateral Plate Mesoderm
- controlled by Tbx transcription factors
What transcription factors control the formation of forelimb? Hindlimb?
Forelimb: Tbx5
Hindlimb: Tbx4
What is the ultimate signal for initiation of limb outgrowth?
Wnt-3
Sources of signal:
- Paraxial (somatic) Mesoderm
- Intermediate Mesoderm
- HOX determines where
- Wnt determines when, regulates Tbx
Amelia? Defective signal?
- failed development of one or more limbs, could be shrunken or deformed
- Meromelia: partial absence of limbs
- Tetra-amelia: failure of all 4 limbs
- linked to defect in Wnt3 signaling
Apical Ectodermal Ridge (AER)?
- condensation of ectodermal cells
- creates a proliferative zone beneath, called the progress zone (0.4mm thick)
- border between dorsal and ventral
- gradient in either direction, differentiates the two
What transcription factors are expressed in the Apical Ectodermal Ridge (AER)?
- Dorsal ectoderm: Wnt-7a
- Ventral ectoderm: Engrailed-1
What happens when the AER is removed?
- removal results in loss of limb element
- remove early: lose radius, ulna, and hand
- remove late: lose hand
Diplopodia?
- congenital anomaly in tetrapods that involves duplication of elements of the foot on the hind limb
- duplication of AER result in supernumerary limbs
Zone of polarizing activity (ZPA)?
- found at distal (posterior) base of limb bud
- produces anterior and posterior limb pattern
- secretes sonic hedge hog (shh)
Acheiropodia?
- autosomal recessive developmental disorder presenting with bilateral congenital amputations of upper and lower extremities and aplasia of hands and feet (hemimelia)
- lack of shh
Polydactyly? post and preaxial?
- congenital physical anomaly in humans and animals having supernumerary fingers or toes
- opposite of oligodactyly (fewer fingers and toes)
- Preaxial: result from ZPA duplication (duplication of 1st or 2nd digit)
- Postaxial: addition of another digit (6th digit)
Tetrapod body plan?
- stylopod: humerus
- zeugopod: ulna and radius, tibia and fibula
- autopod: wrist and fingers, ankle and toes
Progress zone model of proximal-distal axis patterning?
- mesoderm at the distal tip of the limb bud constitutes a progress zone of fixed dimensions, in which cells are receiving progressively more distal positional information over time
- new layers formed in succession
- first PZ, then stylopod, then S and Z; then S,Z and A
Early specification model of proximo-distal axis patterning?
- early limb bud stage, cells are broadly specified to for the three compartments of the limb, the cells undergo expansion before becoming determined to form different skeletal elements
- all layers (S, Z, A) are present from the beginning, but grow and differentiate
Cartilage condensation process?
- cells exit progress zone
- condense or aggregate
- differentiate into chondrocytes
- becomes Cartilaginous Anlage
- Chondrocytes respell
- Interior: differentiated Cartilage
- Exterior: flatted cells Perichondrium
Which limbs develops first?
- forelimb first (arm)
- develops from top down
What process defines the digits?
Interdigital apoptosis
Syndacyly?
- caused by failure of interdigital apoptosis
- two or more digits are fused together
Joint formation process?
- cartilage condensation divided by interzones
- Articular cartilage differentiates
- Joint cavity forms (anlage)
Bone and cartilage development process?
- Bone collar stage: cartilage cells undergo hypertrophy
- Periosteal invasion: periosteum penetrates interior part of bone and replaces cartilage, osteoblast put down mineralized matrix
- Primary Ossification Center
- Creation of Epiphyseal Growth Plate
- Secondary Ossification Center
- Epiphyses
- Apophyses (trochanter)
Layers of Growth plate?
- Resting Cartilage (stem cells)
- Proliferative zone (stacks)
- Hypertrophic zone (bigger chondrocytes)
- Calcification zone (replace cartilage with bone)
- Ossification zone
- grow at fast rate
How many growth plates start to fuse between ages 14-20?
12-15
-stop growing taller once long bones fuse
Brachydactyly?
- abnormal shortening of fingers and toes
- caused by dysfunction or premature closure of growth plate of fingers and toes
What forms muscle development?
- Myoblasts (PAX3 positive cells) migrate from dermomyotome into limb bud and enlarge
- several myoblasts fuse to form a Myotube, which matures into skeletal muscle fiber
- form Dorsal (dmm) and ventral (vmm) muscle masses
Development of Ligaments and Tendons? Gene precursor?
- Scx expressing cells (tendon precursors) arise from sclerotome
- Scx expression (tendon induction) depends on ectoderm, also skeletal condensations
Ligaments and tendons development process?
- Scx expressing tendon progenitors differentiate within limb by FGF signaling
- TGF beta plays a role - tendon progenitors organize between skeletal and muscular tissues
- most tendons depend on presence of muscles to form (extensor and flexor tendons on hand form independent of muscle) - tendon cells signal ridge formation in skeletal tissues
- muscle contraction dictates ridge robusticity
Vascular invasion?
- endothelial cells recruited (from local mesenchyme and somites)
- vasculogenesis: vessels form de novo in embryonic mesenchyme
- angiogenesis: primitive vessels remodeled to form adult networks
- regression (loss of signals) occurs at site of cartilage condensation
Nerve invasion?
- innervation is targeted
- innervation pattern dictated by local pattern signals
- correlation between craniocaudal location of neurons and anteroposterior pattern of muscle innervation
Limb rotation and dermatome formation?
- initially point caudally
- grow at right angle to body
- elbow and knee point outward
- palm and sole toward trunk
- lower limb: rotates cranially significantly
- upper limb: rotates caudally
Bone homologies:
- radius: tibia
- fibula: ulna
