Urodele Limb Regeneration: Mechanisms of Blastema Formation and Growth

Abstract

Urodele salamander limbs regenerate by the accumulation of undifferentiated cells under an apically thickened wound epidermis to form a blastema that grows and redifferentiates into the missing limb parts. Successful regeneration requires several early signals generated within seconds to hours after amputation. The initial accumulation of blastema cells forms largely in the absence of mitosis, after which the cells proliferate rapidly. The accumulation and proliferation of blastema cells is dependent on both nerves and apical epidermis. The nerves and epidermis are linked in a circuit in which nerve axons induce the apical epidermis to make and secrete a mitogen, the anterior gradient protein (AGP), which binds to its receptor Prod1 on the blastema cell surface. Dependence of the epidermis on the nerve for AGP production during regeneration arises during late stages of limb bud development as axons innervate the epidermis, but aneurogenic limbs never acquire axon dependence for the production of AGP after amputation.