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

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

Author information

1
Departments of Pathology and Cell Biology, Neuroscience, Rehabilitation & Regenerative Medicine, and Neurology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA.
2
Departments of Pathology and Cell Biology and Neurology, Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY 10032, USA.
3
Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA.
5
Departments of Pathology and Cell Biology, Neuroscience, Rehabilitation & Regenerative Medicine, and Neurology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: hw350@columbia.edu.

Abstract

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

Comment in

PMID:
30308166
PMCID:
PMC6590086
DOI:
10.1016/j.neuron.2018.09.016
[Indexed for MEDLINE]
Free PMC Article

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