Control of Nerve Sprouting at the Neuromuscular Junction by Extrinsic Local Signals and Intrinsic Neuronal Components

Abstract

Local nerve sprouting is involved in the regulation of synaptogenesis during development and in the adult. During development, it produces terminal arborization and the formation of collaterals. In the adult, sprouting may be involved in synaptic plasticity and is essential to repair and compensatory processes upon lesion. Recent studies have highlighted the high degree of specificity in synaptic connectivity. This has raised the question of how and to what degree and specificity local nerve sprouting is regulated. Here I discuss the contributions of extrinsic and intrinsic factors on nerve sprouting at the neuromuscular junction. At this large peripheral synapse the local environment promotes and guides sprouts through diffusible factors, surface and extracellular matrix molecules, and the processes of terminal Schwann cells. Several growth factors, including IGF-I and II, CNTF and NT-4 can induce ultraterminal sprouting at the adult neuromuscular junction. Among them, insulin-like growth factors are expressed by muscle fibers during development and upon functional inactivation. Blocking experiments in vivo with IGF-binding proteins have revealed that IGF activity is necessary to induce sprouting in paralyzed muscle. Sprouts are guided to denervated endplates by the processes of activated terminal Schwann cells. Recent studies have revealed that in addition to the local environment, the expression of certain growth-associated proteins (GAPs) in motoneurons controls the extent to which nerves sprout. During neonatal development, GAP-43 and CAP-23 are downregulated in motoneurons at the onset of synapse elimination, coincident with the cessation of muscle growth by addition of new muscle fibers which are innervated by collateral sprouts. In the adult, lesions to the nerve reinduce the same proteins. Constitutive expression of these GAPs in adult neurons of transgenic mice fosters spontaneous nerve sprouting and greatly potentiates induced sprouting. In spite of extensive sprouting synapse elimination proceeds to completion in these mice, indicating that the postsynaptic muscle fiber controls the extent to which synapses are formed and eliminated. The view of nerve sprouting in muscle that emerges from these studies is that of a highly regulated process with multiple checkpoints to ensure specificity. It will be interesting to determine to what extent sprouting at other synapses is controlled by similar mechanisms.