Abstract
In vertebrates, functional motoneurons are defined as differentiated neurons that are connected to a central premotor network and activate peripheral muscle using acetylcholine. Generally, motoneurons and muscles develop simultaneously during embryogenesis. However, during Xenopus metamorphosis, developing limb motoneurons must reach their target muscles through the already established larval cholinergic axial neuromuscular system. Here, we demonstrate that at metamorphosis onset, spinal neurons retrogradely labeled from the emerging hindlimbs initially express neither choline acetyltransferase nor vesicular acetylcholine transporter. Nevertheless, they are positive for the motoneuronal transcription factor Islet1/2 and exhibit intrinsic and axial locomotor-driven electrophysiological activity. Moreover, the early appendicular motoneurons activate developing limb muscles via nicotinic antagonist-resistant, glutamate antagonist-sensitive, neuromuscular synapses. Coincidently, the hindlimb muscles transiently express glutamate, but not nicotinic receptors. Subsequently, both pre- and postsynaptic neuromuscular partners switch definitively to typical cholinergic transmitter signaling. Thus, our results demonstrate a novel context-dependent re-specification of neurotransmitter phenotype during neuromuscular system development.
Highlights
The features that define a specific neuronal phenotype are generally conserved between species, are specified early during development, but can undergo adaptive plasticity related to activity after maturation (Demarque and Spitzer, 2012; Borodinsky et al, 2014)
Spatial organization of the appendicular spinal motor column during early metamorphosis Appendicular MNs already project into the hindlimb buds as soon as the latter begin to emerge at stage 48
We report that as early as pre-metamorphosis, de novo appendicular MNs express the Islet transcription factor, exhibit characteristic MN electrical properties and synaptic influences, are involved in locomotor bouts of activity, and project to limb bud muscles to evoke typical post-junctional responses
Summary
The features that define a specific neuronal phenotype are generally conserved between species, are specified early during development, but can undergo adaptive plasticity related to activity after maturation (Demarque and Spitzer, 2012; Borodinsky et al, 2014). The homeodomain-containing protein Islet is the first molecular marker of MN differentiation (Ericson et al, 1992) and induces the later expression of homeobox Hb9, which consolidates the motoneuronal phenotype and participates in MN migration and central motor column formation (Arber et al, 1999) Soon after their specification, MNs express the two typical proteins associated with cholinergic neurotransmission, choline-acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT), enabling them thereafter to activate their muscle targets (Phelps et al, 1991; Chen and Chiu, 1992). In the amphibian Xenopus laevis, the axial and appendicular MNs controlling tail and limb muscles respectively are generated during two separate developmental periods The former develop during pre-hatchling embryonic stages and control larval undulatory tail-based swimming by projecting to and exciting axial myotomes via nicotinic ACh receptor activation (van Mier et al, 1985; Sharpe and Goldstone, 2000). Our results show that during a brief pre-metamorphic period, the emerging limb MNs transiently express a non-cholinergic transmitter phenotype that involves glutamate, while exhibiting all other characteristics of typical vertebrate MNs
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