Development and growth of limb, molecular mechanisms, limb defects

1. Appearance and Initial Development:

- 4th Week: Limb buds become visible as outgrowths from the anterolateral wall. The forelimbs appear first, followed by the hindlimbs 1-2 days later.

- Structure: Initially, the limb buds consist of a mesenchymal core derived from the parietal lateral plate mesoderm, which forms bones and connective tissue. The core is covered by a layer of cuboidal ectoderm.

- Apical Ectodermal Ridge (AER): The ectoderm at the distal end thickens to form the AER, which induces adjacent mesenchyme (progress zone) to remain undifferentiated and rapidly proliferate. The zone of polarizing activity (ZPA) in the posterior mesenchyme maintains the AER and ensures limb asymmetry.

2. Limb Segmentation and Differentiation:

- As the limb grows, cells further from the AER's influence start to differentiate into cartilage and muscle.

- The limb develops in a *proximodistal* direction and is divided into three regions:

  - Stylopod: Humerus and femur

  - Zeugopod: Radius/ulna, tibia/fibula

  - Autopod: Carpals, metacarpals, digits, tarsals, metatarsals

3. Hand and Footplate Formation:

- 6th Week: The terminal parts of the limb buds flatten to form hand and footplates. A circular constriction separates the distal and proximal segments. A second constriction divides the proximal portion into two segments.

- Digit Formation: Fingers and toes form through cell death in the AER, separating it into five segments. These segments guide the formation of digital rays, where mesenchymal condensation forms cartilaginous precursors of the digits, with cell death eliminating tissue between them.

4. Cartilage and Joint Development:

- *6th Week:* Hyaline cartilage models of bones begin to form through chondrocyte activity.

- *Joint Formation:* In areas where cartilage formation halts, joints develop. The condensed mesenchyme in the interzone differentiates into dense fibrous tissue, forming articular cartilage, synovial membranes, menisci, and ligaments within the joint capsule. The joint capsule arises from surrounding mesenchyme.

5. Limb Rotation:

- 7th Week: The limbs rotate in opposite directions:

  - Upper Limb: Rotates 90 degrees laterally, placing extensor muscles on the lateral and posterior surfaces, with the thumbs positioned laterally.

  - Lower Limb: Rotates 90 degrees medially, so that extensor muscles are anterior and the big toe is medial.

6. Ossification:

- *End of Embryonic Period:* Ossification of the bones begins through endochondral ossification. By the 12th week, primary ossification centers are present in all limb bones.

- At Birth: The diaphysis (shaft) of the bones is fully ossified, while the epiphyses (ends) remain cartilaginous, continuing to grow.

7. Muscle Development:

- Source: Limb muscles derive from ventrolateral cells of somites that migrate into the limb buds.

  - Initially, muscle components are segmented based on their somite origin.

  - As the limb buds elongate, the muscle mass splits into *flexor* and *extensor* compartments, with further splitting and fusion forming complex muscle patterns, influenced by connective tissue from lateral plate mesoderm.

8. Nerve Supply:

- Spinal Nerve Penetration: As the limb buds form, the ventral rami of spinal nerves penetrate the mesenchyme.

  - Initially, the ventral rami enter with both dorsal and ventral branches, which later divide into dorsal and ventral divisions. These divisions eventually form the large dorsal and ventral nerves that innervate the limbs.

Conclusion: Discuss the key stages of limb growth and development, highlighting the processes of bone, joint, muscle formation, and limb rotation.