Generating human serotonergic neurons in vitro: Methodological advances

Bioessays. 2016 Nov;38(11):1123-1129. doi: 10.1002/bies.201600127. Epub 2016 Sep 22.


Technologies for deriving human neurons in vitro have transformed our ability to study cellular and molecular components of human neurotransmission. Three groups, including our own, have recently published methods for efficiently generating human serotonergic neurons in vitro. Remarkably, serotonergic neurons derived from each method robustly produce serotonin, express raphe genes, are electrically active, and respond to selective serotonin reuptake inhibitors in vitro. Two of the methods utilize transdifferentiation technology by overexpressing key serotonergic transcription factors. The third and most recent method involves differentiating induced pluripotent stem cells (iPSCs) to serotonergic neurons using developmental patterning cues. In this mini-review, we briefly describe the developmental programs governing serotonergic specification in vivo and how they have been harnessed to achieve serotonergic differentiation in vitro. We discuss the distinct and overlapping features of the recently published methodologies and their value in the context of in vitro disease modeling. Also see the video abstract here.

Keywords: SSRI; antidepressants; direct conversion; iPSC; neuropsychiatric disorders; pluripotent stem cells; serotonergic differentiation.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Transdifferentiation
  • Cellular Reprogramming Techniques / methods*
  • Humans
  • Induced Pluripotent Stem Cells / physiology
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Serotonergic Neurons*
  • Transcription Factors


  • Intercellular Signaling Peptides and Proteins
  • Transcription Factors