Abstract
BackgroundMesencephalic 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.MethodologyWe 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 FindingsWe 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-HT1A-mediated neurotransmitter release, Rgs4, exhibit significant higher expression in ventral hindbrain, compared to midbrain and are target genes of Sim1.ConclusionsThe 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.
Highlights
Cell and neuron subpopulations in the CNS differentiate in stereotypic, defined positions along the anterior-posterior and dorso-ventral axes of the neural tube and exhibit a cell-typespecific transcriptional code [1]
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 dorsal raphe nucleus (DRN) specification acting upstream of Pet1 and tryptophan hydroxylase 2 (Tph2)
Our study underscores that subpopulations of a common neurotransmitter phenotype use distinct combinations of transcription factors to control the expression of shared properties
Summary
Cell and neuron subpopulations in the CNS differentiate in stereotypic, defined positions along the anterior-posterior and dorso-ventral axes of the neural tube and exhibit a cell-typespecific transcriptional code [1]. During development of the CNS, mDA and 5-HT neurons are among the first to emerge [4] Because of their early onset 5-HT neurons are even regarded to play a role in several differentiation processes, acting as a growth and differentiation promoting factor in addition to being a neurotransmitter. Degeneration of mDA is associated with Parkinson’s disease; defects in the serotonergic system are related to depression, obsessive-compulsive disorder, and schizophrenia. 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
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