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Volume 17, Number 11, Issue of June 1, 1997 pp. 4262-4274
Copyright ©1997 Society for Neuroscience

Neurotrophin-3 Promotes the Differentiation of Muscle Spindle Afferents in the Absence of Peripheral Targets

Received Nov. 4, 1996; revised Feb. 27, 1997; accepted March 7, 1997.

Robert A. Oakley¹, Frances B. Lefcort^{2, 5}, Douglas O. Clary^{4, 5}, Louis F. Reichardt⁵, David Prevette³, Ronald W. Oppenheim³, and Eric Frank¹

¹ Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261, ² Department of Biology, Montana State University, Bozeman, Montana 59717, ³ Department of Neurobiology and Anatomy and Neuroscience Program, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, ⁴ Sugen Inc., Redwood City, California 94063, and ⁵ Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, California 94143

The neurons of the dorsal root ganglia (DRG) that supply muscle spindles require target-derived factors for survival. One necessary factor for these neurons is neurotrophin-3 (NT3). To determine whether NT3 can promote the survival of these neurons in the absence of other target-derived factors, we analyzed the effects of exogenous NT3 after early limb bud deletion in the chick. In control embryos, limb bud deletion eliminated ~90% of the trkC-positive (trkC+) neurons in lumbar DRG on the deleted side. In addition, the deletion led to a dramatic loss of collateral sensory projections to motoneurons. Exogenous NT3 restored a normal population of trkC+ neurons in lumbar DRG on the deleted side and increased the number of trkC+ neurons in DRG with normal targets (contralateral lumbar and thoracic). The effect was highly selective; NT3 increased the number of trkC+ neurons without significantly changing the number of either trkA+ or trkB+ neurons. The effect of NT3 was attributable to the rescue of DRG neurons from cell death, because exogenous NT3 reduced the number of pyknotic nuclei without significantly altering proliferation. Analysis of spinal projections showed further that many of the trkC+ neurons rescued by NT3 projected to the ventral spinal cord. These neurons thus had central projections characteristic of muscle spindle afferents. Together, our results indicate that NT3 signaling is both necessary and sufficient for the development of the proprioceptive phenotype, even in the absence of other signals from limb muscle.

Key words: neurotrophins; sensory neurons; muscle spindle afferents; survival; specification; differentiation; development; spinal cord projections; muscle

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