Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons

PLoS One. 2011 Apr 26;6(4):e19239. doi: 10.1371/journal.pone.0019239.


Background: Mesencephalic dopaminergic neurons (mDA) and serotonergic (5-HT) neurons are clinically important ventral neuronal populations. Degeneration of mDA is associated with Parkinson's disease; defects in the serotonergic system are related to depression, obsessive-compulsive disorder, and schizophrenia. Although these neuronal subpopulations reveal positional and developmental relationships, the developmental cascades that govern specification and differentiation of mDA or 5-HT neurons reveal missing determinants and are not yet understood.

Methodology: We investigated the impact of the transcription factor Sim1 in the differentiation of mDA and rostral 5-HT neurons in vivo using Sim1-/- mouse embryos and newborn pups, and in vitro by gain- and loss-of-function approaches.

Principal findings: We show a selective significant reduction in the number of dorsal raphe nucleus (DRN) 5-HT neurons in Sim1-/- newborn mice. In contrast, 5-HT neurons of other raphe nuclei as well as dopaminergic neurons were not affected. Analysis of the underlying molecular mechanism revealed that tryptophan hydroxylase 2 (Tph2) and the transcription factor Pet1 are regulated by Sim1. Moreover, the transcription factor Lhx8 and the modulator of 5-HT(1A)-mediated neurotransmitter release, Rgs4, exhibit significant higher expression in ventral hindbrain, compared to midbrain and are target genes of Sim1.

Conclusions: The results demonstrate for the first time a selective transcription factor dependence of the 5-HT cell groups, and introduce Sim1 as a regulator of DRN specification acting upstream of Pet1 and Tph2. Moreover, Sim1 may act to modulate serotonin release via regulating RGS4. Our study underscores that subpopulations of a common neurotransmitter phenotype use distinct combinations of transcription factors to control the expression of shared properties.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers / metabolism
  • Cell Differentiation* / genetics
  • Cell Line
  • Cell Lineage
  • Dopamine / metabolism
  • Genetic Association Studies
  • Mesencephalon / metabolism
  • Mice
  • Models, Biological
  • Mutation / genetics
  • Neurons / cytology*
  • Neurons / enzymology
  • Phenotype
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Raphe Nuclei / cytology*
  • Raphe Nuclei / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serotonin / metabolism
  • Tyrosine 3-Monooxygenase / metabolism
  • Up-Regulation / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers
  • RNA, Messenger
  • Repressor Proteins
  • Sim1 protein, mouse
  • Serotonin
  • Tyrosine 3-Monooxygenase
  • Dopamine