PERIPHERAL TARGET REGULATION OF THE DEVELOPMENT AND SURVIVAL OF SPINAL SENSORY AND MOTOR-NEURONS IN THE CHICK-EMBRYO

Unilateral limb-bud removal (LBR) before the outgrowth of sensory or m otor neurons to the leg of chick embryos was used to examine the role of limb (target)-derived signals in the development and survival of lu mbar motoneurons and sensory neurons in the dorsal root ganglia (DRG). After LBR, motor and sensory neurons underwent normal initial histolo gical differentiation, and cell growth in both populations was unaffec ted. Before their death, target-deprived motoneurons also expressed a cell-specific marker, the homeodomain protein islet-1. Proliferation o f sensory and motor precursor cells was also unaffected by LBR, and th e migration of neural crest cells to the DRG and of motoneurons into t he ventral horn occurred normally. During the normal period of program med cell death (PCD), increased numbers of both sensory and motor neur ons degenerated after LBR. However, whereas motoneuron loss increased by 40-50% (90% total), only similar to 25% more sensory neurons degene rated after LBR. A significant number of the surviving sensory neurons projected to aberrant targets in the tail after LBR, and many of thes e were lost after ablation of both the limb and tail. Treatment with n eurotrophic factors (or muscle extract) rescued sensory and motor neur ons from cell death after LBR without affecting precursor proliferatio n of either population. Activity blockade with curare failed to rescue motoneurons after LBR, and combined treatment with curare plus muscle extract was no more effective than muscle extract alone, Treatment wi th the antioxidant N-acetylcysteine rescued motoneurons from normal ce ll death but not after LBR. Two specific inhibitors of the interleukin beta 1 converting enzyme (ICE) family of cysteine proteases also fail ed to prevent motoneuron death after LBR. Taken together these data pr ovide definitive evidence that the loss of spinal neurons after LBR ca nnot be attributed to altered proliferation, migration, or differentia tion. Rather, in the absence of limb-derived trophic signals, the affe cted neurons fail to survive and undergo PCD. Although normal cell dea th and cell death after target deprivation share many features in comm on, the intracellular pathways of cell death in the two may be distinc t.