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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.

Sim1 Is a Novel Regulator in the Differentiation of Mouse Dorsal Raphe Serotonergic Neurons