The possibility has been investigated that nerves, which promote mitotic activity during the growth phase of limb regeneration, may also release factors upon injury to stimulate the cellular events during the initiation of regeneration. These events have been compared in control, innervated limb stumps and in limbs denervated for various periods before amputation. Wound closure occurred in an essentially normal manner in limbs denervated at the time of amputation but frequently occurred at reduced rates or not at all in limb stumps denervated 5 days before amputation. Tissue loss and various degrees of morphological regression were seen in many of the predenervated limb stumps, including all of those denervated for 6 days or more before amputation. Evidence is presented which suggests that regression may result from a combination of the denervated state and disturbance to the limb's vascular system. Limbs predenervated 2-10 days before amputation were fixed 7 days after amputation and examined histologically. All limb stumps, including those involved in regression, showed tissue dissociation and cellular dedifferentiation. Autoradiography revealed that the dedifferentiation involved DNA synthesis in both denervated and innervated limbs. Seven days after amputation, DNA-labeling indices in limb stumps predenervated 2 or 4 days were similar to those of control limbs, but labeling indices were significantly reduced in limbs predenervated 6 or more days. The results are assessed in light of the state of nerve degeneration in the limbs at the time of amputation and are discussed in terms of what is known regarding nerve-derived growth-promoting substances.
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