Adult ciliary neurotrophic factor receptors help maintain facial motor neuron choline acetyltransferase expression in vivo following nerve crush

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Ciliary neurotrophic factor (CNTF) is a potent neuroprotective factor for embryonic motor neurons in vitro (Lindsay et al., 1994). In vivo, CNTF administration protects motor neurons after early postnatal peripheral nerve lesion (Sendtner et al., 1990), in genetic models of motor neuron disease (Sendtner et al., 1992a; Ikeda et al., 1995; Sagot et al., 1995), and during developmental naturally occurring motor neuron death (Oppenheim et al., 1991), suggesting that endogenous CNTF receptor signaling may maintain motor neurons during development and in adulthood.
To determine directly the role(s) of endogenous CNTF receptors in motor neuron maintenance, the receptors must be manipulated in vivo. CNTF receptor α (CNTFRα) is an essential ligand binding subunit of the CNTF receptor, which is composed of CNTFRα, leukemia inhibitory factor receptor β (LIFRβ), and gp130 (Davis et al., 1993a). Although LIFRβ and gp130 are found in other related receptors, CNTFRα is unique to CNTF receptors and is required for all known forms of CNTF receptor signaling, regardless of the ligands or signaling pathways involved (Davis et al., 1993a; Elson et al., 2000; Derouet et al., 2004). Therefore, CNTFRα disruption is the best method for comprehensively determining endogenous CNTF receptor function.
Unconditional disruption of the CNTFRα gene in mice leads to uniform death within 24 hours of birth, accompanied by motor neuron loss (DeChiara et al., 1995). Thus, endogenous CNTF receptor signaling is essential for embryonic motor neuron survival/development. However, it is particularly important to identify and characterize the endogenous mechanisms maintaining adult motor neurons because such mechanisms may serve as therapeutic targets for adult‐onset motor neuron diseases and trauma. The perinatal death of the unconditional CNTFRα knockout mice precludes their use for adult studies. Moreover, to identify adult functions independent of potential developmental effects, adult‐onset disruption is required. Therefore, we have used Cre/loxP technology to deplete CNTFRα in adult facial motor neurons by combining an adult inducible Cre recombinase (Cre) gene construct and floxed CNTFRα mice (Lee et al., 2013a). We found that, in contrast to the effects of CNTFRα disruption during development, adult disruption did not affect motor neuron survival (Lee et al., 2013a), indicating that the motor neuron CNTF receptors do not play an essential role in the survival of noninsulted adult motor neurons.
Adult facial motor neurons, unlike early postnatal motor neurons, do not die following nerve crush (Gilad et al., 1996; Kuzis et al., 1999; Lee et al., 2013a), and this serves as a model to identify endogenous mechanisms maintaining adult motor neurons after insult. Our adult CNTFRα disruption did not affect motor neuron survival following nerve crush (Lee et al., 2013a), indicating that the receptors are not essential for the survival of the lesioned motor neurons.
However, several studies have indicated that CNTF promotes expression of choline acetyltransferase (ChAT) in cultured motor neurons (Magal et al., 1991; Glicksman et al., 1993; Wong et al., 1993; Kato and Lindsay, 1994; Zurn, 1994), likely independent of its effects on motor neuron survival (Wong et al., 1993; Zurn, 1994). These data raise the interesting possibility that endogenous CNTF receptors, although not essential for adult motor neuron survival, play an important role by helping maintain this functionally critical neurotransmitter enzyme in adult motor neurons.
To address this question directly in adult motor neurons in vivo, the experiments reported here used the same adult‐onset CNTFRα disruption model with facial nerve crush. The effect of CNTFRα disruption on ChAT was examined in intact and nerve crush‐lesioned motor neurons.
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