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

Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):E2486-E2493. doi: 10.1073/pnas.1615372114. Epub 2017 Mar 7.


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.

Keywords: Artemin; fluorescence-activated cell sorting; motor neuron; neurotrophic factor; screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • 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
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neurons / cytology
  • Motor Neurons / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Syndecan-3 / genetics
  • Syndecan-3 / metabolism


  • Artn protein, mouse
  • Ciliary Neurotrophic Factor
  • Ciliary Neurotrophic Factor Receptor alpha Subunit
  • Gfra3 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Tissue Proteins
  • Sdc3 protein, mouse
  • Syndecan-3
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met