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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-03, Vol.114 (12), p.E2486-E2493
• Main Authors: Schaller, Sébastien, Buttigieg, Dorothée, Alory, Alysson, Jacquier, Arnaud, Barad, Marc, Merchant, Mark, Gentien, David, de la Grange, Pierre, Haase, Georg
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Biological Sciences; Cell Survival; Ciliary Neurotrophic Factor - metabolism; Ciliary Neurotrophic Factor Receptor alpha Subunit - genetics; Ciliary Neurotrophic Factor Receptor alpha Subunit - metabolism; Female; Flow Cytometry; Glial Cell Line-Derived Neurotrophic Factor Receptors - genetics; Glial Cell Line-Derived Neurotrophic Factor Receptors - metabolism; Hepatocyte Growth Factor - metabolism; Humans; Medical screening; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons - cytology; Motor Neurons - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; PNAS Plus; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Rodents; Survival; Syndecan-3 - genetics; Syndecan-3 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1615372114

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 CNTFRα; and Artemin acts as the first survival factor for parasympathetic preganglionic motor neurons through GFRα3/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.