Subtype Diversification and Synaptic Specificity of Stem Cell-Derived Spinal Interneurons

Neuron. 2018 Oct 10;100(1):135-149.e7. doi: 10.1016/j.neuron.2018.09.016.


Neuronal diversification is a fundamental step in the construction of functional neural circuits, but how neurons generated from single progenitor domains acquire diverse subtype identities remains poorly understood. Here we developed an embryonic stem cell (ESC)-based system to model subtype diversification of V1 interneurons, a class of spinal neurons comprising four clades collectively containing dozens of molecularly distinct neuronal subtypes. We demonstrate that V1 subtype diversity can be modified by extrinsic signals. Inhibition of Notch and activation of retinoid signaling results in a switch to MafA clade identity and enriches differentiation of Renshaw cells, a specialized MafA subtype that mediates recurrent inhibition of spinal motor neurons. We show that Renshaw cells are intrinsically programmed to migrate to species-specific laminae upon transplantation and to form subtype-specific synapses with motor neurons. Our results demonstrate that stem cell-derived neuronal subtypes can be used to investigate mechanisms underlying neuronal subtype specification and circuit assembly.

Keywords: Renshaw cell; V1 interneuron; differentiation; embryonic stem cells; in vitro; motor neuron; neurons; spinal cord; subtype; synaptic specificity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Interneurons / cytology*
  • Interneurons / metabolism
  • Mice
  • Motor Neurons / cytology
  • Motor Neurons / metabolism
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Neurogenesis / physiology*
  • Spinal Cord / cytology
  • Spinal Cord / embryology
  • Spinal Cord / metabolism
  • Synapses / metabolism*