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Direct conversion of human fibroblasts to induced serotonergic neurons.

Abstract
Serotonergic (5HT) neurons exert diverse and widespread functions in the brain. Dysfunction of the serotonergic system gives rise to a variety of mental illnesses including depression, anxiety, obsessive compulsive disorder, autism and eating disorders. Here we show that human primary fibroblasts were directly converted to induced serotonergic (i5HT) neurons by the expression of Ascl1, Foxa2, Lmx1b and FEV. The transdifferentiation was enhanced by p53 knockdown and appropriate culture conditions including hypoxia. The i5HT neurons expressed markers for mature serotonergic neurons, had Ca(2+)-dependent 5HT release and selective 5HT uptake, exhibited spontaneous action potentials and spontaneous excitatory postsynaptic currents. Application of serotonin significantly increased the firing rate of spontaneous action potentials, demonstrating the functional utility of i5HT neurons for studying serotonergic neurotransmission. The availability of human i5HT neurons will be very useful for research and drug discovery on many serotonin-related mental disorders.
AuthorsZ Xu, H Jiang, P Zhong, Z Yan, S Chen, J Feng
JournalMolecular psychiatry (Mol Psychiatry) Vol. 21 Issue 1 Pg. 62-70 (Jan 2016) ISSN: 1476-5578 [Electronic] England
PMID26216300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • FEV protein, human
  • FOXA2 protein, human
  • LIM homeobox transcription factor 1 beta
  • LIM-Homeodomain Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Hepatocyte Nuclear Factor 3-beta
  • Serotonin
  • Calcium
Topics
  • Action Potentials (physiology)
  • Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
  • Calcium (metabolism)
  • Cell Transdifferentiation (physiology)
  • Cytological Techniques (methods)
  • DNA-Binding Proteins (genetics, metabolism)
  • Excitatory Postsynaptic Potentials (physiology)
  • Fibroblasts (physiology)
  • Gene Knockdown Techniques
  • Hepatocyte Nuclear Factor 3-beta (genetics, metabolism)
  • Humans
  • LIM-Homeodomain Proteins (genetics, metabolism)
  • Nuclear Proteins (genetics, metabolism)
  • Serotonergic Neurons (physiology)
  • Serotonin (metabolism)
  • Transcription Factors (genetics, metabolism)
  • Tumor Suppressor Protein p53 (genetics, metabolism)

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