| 1 | 《公共科学图书馆•综合》2011年1 6:e19239 |
|---|---|
| PMID | 21541283 |
| Title | Sim1不vel regulator in the differentiation of mouse dorsal raphe serotonergic neurons. |
| Abstract | 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, andschizophrenia. 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. We investigated the impact of the transcription factorSIM1in the differentiation of mDA and rostral 5-HT neurons in vivo usingSIM1-/- mouse embryos and newborn pups, and in vitro by gain- and loss-of-function approaches. We show a selective significant reduction in the number of dorsal raphe nucleus (DRN) 5-HT neurons inSIM1-/- 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 bySIM1. 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 ofSIM1. The results demonstrate for the first time a selective transcription factor dependence of the 5-HT cell groups, and introduceSIM1as a regulator of DRN specification acting upstream of Pet1 and Tph2. Moreover,SIM1may 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. |
| SCZ Keywords | schizophrenia |