title: Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Department for Neuroanatomy, Georg-August-University Goettingen, Goettingen, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Osterberg
authors.forename: Michael
authors.initials: M
authors.lastname: Wiehle
authors.forename: Oliver
authors.initials: O
authors.lastname: Oehlke
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heidrich
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Fan
authors.forename: Kerstin
authors.initials: K
authors.lastname: Krieglstein
authors.forename: Eleni
authors.initials: E
authors.lastname: Roussa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage; D004298:Dopamine / Q000378:metabolism; D056726:Genetic Association Studies; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D010641:Phenotype; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D004298:Dopamine; D012333:RNA, Messenger; D012097:Repressor Proteins; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; C101750:Sim1 protein, mouse