Abstract
Acetylcholinesterase (AChE) and agrin, a heparan-sulfate proteoglycan, reside in the basal lamina of the neuromuscular junction (NMJ) and play key roles in cholinergic transmission and synaptogenesis. Unlike most NMJ components, AChE and agrin are expressed in skeletal muscle and α-motor neurons. AChE and agrin are also expressed in various other types of cells, where they have important alternative functions that are not related to their classical roles in NMJ. In this review, we first focus on co-cultures of embryonic rat spinal cord explants with human skeletal muscle cells as an experimental model to study functional innervation in vitro. We describe how this heterologous rat-human model, which enables experimentation on highly developed contracting human myotubes, offers unique opportunities for AChE and agrin research. We then highlight innovative approaches that were used to address salient questions regarding expression and alternative functions of AChE and agrin in developing human skeletal muscle. Results obtained in co-cultures are compared with those obtained in other models in the context of general advances in the field of AChE and agrin neurobiology.
Highlights
Acetylcholineesterase (AChE) and agrin, a heparan sulfate proteoglycan, are important for termination of neuromuscular transmission and maintenance of the neuromuscular junction (NMJ), respectively [1,2,3,4,5,6]
In order to get a more detailed insight into species-specific differences in NMJ synaptogenesis, we examined whether postsynaptic differentiation of NMJ in cultured human myotubes can be induced in the absence of motor neurons
While agrin or the conditioned medium collected from co-cultures of contracting human myotubes and embryonic rat spinal cord promote nicotinic acetylcholine (ACh) receptors (nAChRs) clustering in aneural human myotubes [82,83], such treatment does not seem to be capable of fully supporting their further differentiation into spontaneously contracting myofibers
Summary
Acetylcholineesterase (AChE) and agrin, a heparan sulfate proteoglycan, are important for termination of neuromuscular transmission and maintenance of the neuromuscular junction (NMJ), respectively [1,2,3,4,5,6]. In addition to these canonical roles in NMJ, AChE and agrin have alternative functions that are not related to NMJ and cholinergic transmission [7,8,9,10,11]. Canonical and alternative roles of AChE and agrin have been investigated using many different in vitro and in vivo experimental approaches. We provide description of biological characteristics and methodological aspects of this model and discuss them in the context of AChE and agrin neurobiology
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