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The human response to serious cutaneous damage is limited to relatively primitive wound healing, whereby collagenous scar tissue fills the wound bed. Scars assure structural integrity at the expense of functional regeneration. In contrast, axolotls have the remarkable capacity to functionally regenerate full thickness wounds. Here, we identified a novel role for SALL4 in regulating collagen transcription after injury that is essential for perfect skin regeneration in axolotl. Furthermore, we identify miR-219 as a molecular regulator of Sall4 during wound healing. Taken together, our work highlights one molecular mechanism that allows for efficient cutaneous wound healing in the axolotl.