Journal of Neuroscience, Vol 12, 3849-3861, Copyright © 1992 by Society for Neuroscience
The downregulation of growth-associated proteins in motoneurons at the onset of synapse elimination is controlled by muscle activity and IGF1
P Caroni and M Becker
Friedrich Miescher Institute, Basel, Switzerland.
Axonal growth during development and regeneration coincides with the
expression of growth-associated proteins (GAPs), including GAP-43 and
tubulin-alpha 1. Following contact with the target region and
synaptogenesis, GAPs are downregulated. However, high levels of GAP-43 are
expressed in some neurons in the adult CNS, indicating that its function
may not be restricted to axonal growth. To define the type of signals that
regulate GAP levels during development, we have determined whether GAP
downregulation coincides with a defined phase of synapse development and
whether it is controlled by the postsynaptic target. Levels of GAP-43 mRNA
in spinal motoneurons and protein at the neuromuscular junction were
analyzed in the developing neuromuscular system of chick and rat. In both
species, GAP-43 mRNA declined rapidly at a time corresponding to the onset
of synapse elimination, and nerve terminal GAP-43 immunoreactivity became
undetectable with a delay of 2- 3 d. In rat motoneurons, GAP-43 and
tubulin-alpha 1 mRNA levels declined with a similar time course, indicating
that at least two GAPs are downregulated at the same time. Blockade of
neuromuscular transmission with either a pre- or a postsynaptically acting
toxin prevented GAP downregulation, indicating that target activity affects
GAP mRNA levels in motoneurons. Finally, counteracting the activity-
dependent decline of muscle insulin-like growth factors during synapse
elimination by local subcutaneous injections prevented motoneuron GAP
downregulation, suggesting that these growth factors may be involved in the
regulation of motoneuron GAPs by the muscle. These results demonstrate that
motoneurons undergo target-sensitive changes in GAPs at the onset of
synapse elimination. In addition, these results raise the possibility that
termination of a presynaptic growth mode may be a prerequisite for synapse
elimination.
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