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Novel combinatorial screening identifies neurotrophic factors for selective classes of motor neurons.

ABSTRACT: Numerous neurotrophic factors promote the survival of developing motor neurons but their combinatorial actions remain poorly understood; to address this, we here screened 66 combinations of 12 neurotrophic factors on pure, highly viable, and standardized embryonic mouse motor neurons isolated by a unique FACS technique. We demonstrate potent, strictly additive, survival effects of hepatocyte growth factor (HGF), ciliary neurotrophic factor (CNTF), and Artemin through specific activation of their receptor complexes in distinct subsets of lumbar motor neurons: HGF supports hindlimb motor neurons through c-Met; CNTF supports subsets of axial motor neurons through CNTFR?; and Artemin acts as the first survival factor for parasympathetic preganglionic motor neurons through GFR?3/Syndecan-3 activation. These data show that neurotrophic factors can selectively promote the survival of distinct classes of embryonic motor neurons. Similar studies on postnatal motor neurons may provide a conceptual framework for the combined therapeutic use of neurotrophic factors in degenerative motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and spinobulbar muscular atrophy.

SUBMITTER: Schaller S

PROVIDER: S-EPMC5373341 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Novel combinatorial screening identifies neurotrophic factors for selective classes of motor neurons.

Schaller Sébastien S Buttigieg Dorothée D Alory Alysson A Jacquier Arnaud A Barad Marc M Merchant Mark M Gentien David D de la Grange Pierre P Haase Georg G

Proceedings of the National Academy of Sciences of the United States of America 20170307 12

Numerous neurotrophic factors promote the survival of developing motor neurons but their combinatorial actions remain poorly understood; to address this, we here screened 66 combinations of 12 neurotrophic factors on pure, highly viable, and standardized embryonic mouse motor neurons isolated by a unique FACS technique. We demonstrate potent, strictly additive, survival effects of hepatocyte growth factor (HGF), ciliary neurotrophic factor (CNTF), and Artemin through specific activation of their ...[more]

PMID: 28270618

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Project description:BACKGROUND: Ageing is associated with gastrointestinal dysfunction, which can have a major impact on quality of life of the elderly. A number of changes in the innervation of the gut during ageing have been reported, including neuronal loss and degenerative changes. Evidence indicates that reactive oxygen species (ROS) are elevated in ageing enteric neurons, but that neurotrophic factors may reduce generation of neuronal ROS. Two such factors, glial cell line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) have also been found to protect enteric neurons against oxidative stress induced cell death of enteric ganglion cells in vitro. We have investigated the possible roles of neurotrophic factors further, by examining their expression in the gut during ageing, and by analysing their effects on antioxidant enzyme production in cultures of enteric ganglion cells. RESULTS: Analysis of the expression of GDNF and its receptors c-Ret and GFR ??-?1 in rat gut by RT-PCR showed that expression continues throughout life and into ageing, in both ad libitum(AL) and calorically-restricted (CR) animals. Levels of expression of GDNF and GFR ??-?1 were elevated in 24?month AL animals compared to 24?month CR animals, and to 24 CR and 6?month control animals respectively. The related factor Neurturin and its receptor GFR ??-?2 were also expressed throughout life, the levels of the GFR - ?-2(b) isoform were reduced in 24?m AL animals. Immunolabelling showed that c-Ret and GFR ??-?1 proteins were expressed by myenteric neurons in ageing animals. GDNF, but not NT-3, was found to increase expression of Cu/Zn superoxide dismutase and catalase by cultured enteric ganglion cells. CONCLUSIONS: The neurotrophic factors GDNF and neurturin and their receptors continue to be expressed in the ageing gut. Changes in the levels of expression of GDNF , GFR ?-1 and GFR ?-2(b) isoform occurred in 24?m AL animals. GDNF, but not NT-3, increased the levels of antioxidant enzymes in cultured enteric ganglion cells, indicating a possible mechanism for the reported protective effect of GDNF against menadione-induced neuronal apoptosis in the ageing gut. Together these data suggest that GDNF family members may play a protective role in the gut throughout life, and support the suggestion that dysregulation of neurotrophic factor support could contribute to neuronal ageing in the gut.

Dataset Information

Novel combinatorial screening identifies neurotrophic factors for selective classes of motor neurons.

Publications

Novel combinatorial screening identifies neurotrophic factors for selective classes of motor neurons.

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