Neurotrophins regulate agrin-induced postsynaptic differentiation

Abstract

The precise orchestration of synaptic differentiation is critical for efficient information exchange in the nervous system. The nerve-muscle synapse forms in response to agrin, which is secreted from the motor nerve terminal and induces the clustering of acetylcholine receptors (AChRs) and other elements of the postsynaptic apparatus on the subjacent muscle cell surface. In view of the highly restricted spatial localization and the plasticity of neuromuscular junctions, it seems likely that synapse formation and maintenance are regulated by additional, as-yet-unidentified factors. Here, we tested whether neurotrophins modulate the agrin-induced differentiation of postsynaptic specializations. We show that both brain-derived neurotrophic factor ( The formation, maintenance, and plasticity of synaptic connections is essential for the proper functioning of the nervous system. A hallmark of fast synapses is the precise spatial registration of the nerve terminal and postsynaptic apparatus. This alignment has been long appreciated in nerve-muscle synapses (1) and has also been demonstrated in a wide range of neuronal synapses (2). Synaptic structure also is tightly regulated: a large number of the synaptic connections initially formed in both the central nervous system (CNS) and the periphery are pruned by the process of synapse elimination.

Evidence for the involvement of neurotrophins in muscle transdifferentiation and acetylcholine receptor transformation in the esophagus of Myf5−/−:MyoD−/− and NT‐3−/− embryos

“…These receptors previously were found to be expressed in the transdifferentiating muscle of the esophagus, and their role in smooth-to-skeletal muscle transdifferentiation is suggested (Fu et al, 1997;Wells et al, 1999;Wö rl and Neuhubert, 2000;Raab et al, 2003). In accordance with these findings, our data demonstrate a clear expression of TrkB and TrkC in the control esophageal muscle (Fig.…”

“…Recent studies support the concept of an intrinsic regulation of postsynaptic differentiation (Dahm and Landmesser, 1991;Wells et al, 1999;Wö rl and Neuhuber, 2000). Apparently, clusters of acetylcholine receptors are demonstrated even on uninnervated chick myotubes in vitro (Dahm and Landmesser, 1991), suggesting that the clustering mechanism is intrinsic to the muscle fiber and, therefore, independent of neuronal influence.…”

“…Skeletal muscle-secreted neurotrophins and their high affinity receptors appear to be essential in the process of intrinsic regulation of postsynaptic differentiation (Wells et al, 1999;Wö rl and Neuhuber, 2000). To assess whether there were differences in neurotrophic factor expression between the nontransdifferentiating SM of the double-mutant esophagi and the transdifferentiating muscle of the control esophagi, several antibodies to neurotrophins and their receptors were used on transverse sections of E15.5-E18.5 esophagi of both genotypes.…”

“…To assess whether there were differences in neurotrophic factor expression between the nontransdifferentiating SM of the double-mutant esophagi and the transdifferentiating muscle of the control esophagi, several antibodies to neurotrophic factors (i.e., those secreted by the skeletal muscle with an influence on motor innervation; Fu et al, 1997;Wells et al, 1999) were used on transverse sections of E15.5-E18.5 esophagi of both genotypes ( Fig. 3A-F and data not shown).…”

“…Apparently, clusters of acetylcholine receptors are demonstrated even on uninnervated chick myotubes in vitro (Dahm and Landmesser, 1991), suggesting that the clustering mechanism is intrinsic to the muscle fiber and, therefore, independent of neuronal influence. (Wells et al, 1999;Wö rl and Neuhuber, 2000).…”