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Title: Dopaminergic subset specification as a model for molecular mechanisms of neural vulnerability in Parkinson's Disease      
keywords:
Transcriptome or Gene expression
ID:
PRJNA246426
description:
Mesodiencephalic dopaminergic (mdDA) neurons critically regulate locomotory behavior and emotion, and dysfunction is associated with psychiatric and neurodegenerative diseases, including Parkinson's Disease (PD). A pathological hallmark of PD is the specific degeneration of Substantia Nigra (SN) neurons, whereas Ventral Tegmental Area (VTA) neurons are relatively unaffected. Differential molecular programming of the developing SN versus VTA may underly this specific vulnerability, and indeed molecularly distinct mdDA subsets have been identified during development. Driven by the hypothesis that the molecular signature of the SN and VTA originates from differential developmental programming and position along the rostral/caudal axis, we performed genome-wide expression profiling of FACS-purified rostral versus caudal mdDA neurons. Here, we present the distinct transcriptomes of these mdDA subsets and demonstrate how, on a genome-wide scale: 1) transcription factor regulation relates to developmental position, 2) rostral and caudal mdDA neurons differ in their functional genome, 3) the molecular signature of rostral versus caudal mdDA neurons relates to the SN versus VTA molecular profile in adult mice and human and 4) human homologues of rostrally enriched genes are mostly downregulated in the SN of PD patients. Our analyses substantiate the relationship of developmental positions with the SN versus VTA distinction in adult, and suggest cross-species conservation of molecular programs. Driven by these observations, we present 69 target genes that are rostral enriched and downregulated in PD, and thus provide new leads for the investigation of both the complex coding of developing mdDA subsets and and the molecular mechanisms underlying subset-specific vulnerability in PD. Overall design: Microarrray analysis was performed in quadruple. Each biological replicate consisted of a pool of Pitx3(Gfp/+) rostral or caudal samples from 5-7 individual embyros that were interleaved across litters to account for litter-to-litter variation, or a pool of Gfp-negative cells from the same specimens as a common reference.
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA246426
authentication:
none
authorization:
none
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject