Retinoic acid (RA) is a key morphogenetic regulator in the limb regeneration process of axolotls and other amphibians. When a blastema from a distal limb region—such as the wrist—is transplanted onto a proximal amputation site, the host normally regenerates the missing proximal segments while the blastema regenerates only the wrist structures. However, if the blastema is treated with RA before grafting, it acquires new proximal positional information, leading to regeneration of a complete limb without requiring the host to fill in the proximal gap.

Mechanism of RA-Induced Proximalization and Limb Regeneration

• Proximalization of Blastema Cells:
  RA treatment respecifies the blastema cells to adopt a more proximal positional identity along the proximodistal axis of the limb. This reprogramming overrides their original distal identity and equips them to regenerate structures normally found proximally, such as the stylopod (upper arm) and zeugopod (forearm).

• Activation of Hox Genes:
  RA regulates the expression of Hox genes, which are critical for encoding positional information during limb patterning. Differential activation of these genes across the blastema fabricates spatial cues necessary for correct pattern formation and segment identity along the limb.

• Dose-Dependent Morphogen Role:
  RA functions in a dose-dependent manner, whereby higher concentrations support more pronounced proximalization and pattern duplications.

• Outcome in Limb Regeneration:
  The RA-treated blastema regenerates a full limb autonomously, preventing the host from regenerating the proximal segments, thereby illustrating RA’s transformative effect in resetting positional commands within the regenerative tissue.

Why Other Options Are Incorrect

• (2) Distalization of blastema: RA induces proximalization, not distalization, so this is incorrect.

• (3) Blocking FGF receptors: RA does not block FGF receptors; FGFs work synergistically with positional cues like RA for proper limb development.

• (4) Vigorous proliferation: While RA may influence cell proliferation, its primary role in this context is positional re-specification rather than just promoting proliferation.

Summary

Retinoic acid treatment of wrist blastemas in axolotl limb regeneration proximalizes the cells and activates key positional Hox genes, resulting in the regeneration of a complete limb. This illustrates RA’s crucial role as a morphogen in reprogramming positional identity to direct complex limb morphogenesis during regeneration.

Final Answer:
(1) helps in proximalization of the blastema and activates the Hox genes differentially across the blastema.