RNA-Seq analysis of mouse dopamine neurons identifies transcriptional repression of PlexinC1 by Lmx1a and Lmx1b
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ABSTRACT:
PROVIDER: PRJEB22236 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2099690_1.fastq.gz | Fastqsanger.gz | |||
| ERR2099690_2.fastq.gz | Fastqsanger.gz | |||
| ERR2099700_1.fastq.gz | Fastqsanger.gz | |||
| ERR2099700_2.fastq.gz | Fastqsanger.gz | |||
| ERR2099691_1.fastq.gz | Fastqsanger.gz |
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Project description:In order to identify axon guidance molecules regulated by Lmx1a and Lmx1b RNA sequencing was performed on three biological replicates for the control and four biological replicates for Lmx1a/b cKO mice. For each sample, two technical replicates were performed. For each E15.5 embryo used, VTA and SNpc were dissected from 8 antero- posterior levels across the entire dopaminergic domain as revealed by TH immnostaining. Following RNA extraction, RNAseq libraries were constructed using the Illumina TruSeq Stranded RNA protocol with oligo dT pulldown and sequenced on Illumina HiSeq2500 by 150-bp paired-end sequencing. One sample was excluded before the sequencing because the amount of RNA was too low to measure the RNA quality.
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Project description:Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons provides a promising strategy for brain repair in Parkinson’s disease (PD). However, essential refinement of differentiation protocols will require deeper interrogation of mesDA neuron lineage development. Here we studied neuronal development at the transcriptome-wide expression level by single-cell RNA sequencing of cells expressing the mesDA neuron transcription factor determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons. The combined ablation of Lmx1a and Lmx1b in mice disrupted both STN and mesDA neural development, while a distinct transcription factor set defined progenitors developing into STN neurons. Importantly, markers previously used to guide stem cell engineering into human mesDA neurons are shared between the two lineages. These results have important implications for stem cell engineering into mesDA neurons for cell replacement therapy in PD.
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Project description:RNA-Seq analysis of mouse dopamine neurons identifies transcriptional repression of PlexinC1 by Lmx1a and Lmx1b
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Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.
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Project description:The LIM homeodomain transcription factor Lmx1a is a very potential inducer of stem cells towards dopaminergic neurons. Despite several studies on the function of this gene, the exact in vivo role of Lmx1a in mesodiencephalic dopamine (mdDA) neuronal specification is still not understood. To analyze the genes functioning downstream of Lmx1a, we performed expression microarray analysis of LMX1A overexpressing MN9D dopaminergic cells. Several interesting regulated genes were identified, based on their regulation in other, previously generated expression arrays, and their expression pattern in the developing mdDA neuronal field. Post analysis through in vivo expression analysis in Lmx1a mouse mutant (drJ/drJ) embryos demonstrated a clear decrease in expression of the genes Grb10 and Rgs4, in and adjacent to the rostral and dorsal mdDA neuronal field and within the Lmx1a expression domain. Interestingly, the DA marker Vmat2 was significantly up-regulated as a consequence of increased LMX1A dose, and subsequent analysis on Lmx1a mutant E14.5 and adult tissue revealed a significant decrease in Vmat2 expression in mdDA neurons. Taken together, microarray analysis of an LMX1A overexpression cell system resulted in the identification of novel downstream targets of Lmx1A in mdDA neurons: Grb10, Rgs4 and Vmat2. RNA was isolated from MN9D cells. Each experimental sample consisted of a RNA pool derived from 3 separate 10-cm dishes containing Lmx1a overexpressing MN9D cells (transfected with pcDNA3.1(-)-Lmx1a). microarray analysis was performed in triplicate, each experimental sample was hybridized to the same reference pool of RNA derived from 9 10-cm dishes containing control MN9D cells (transfected with empty pcDNA3.1(-)). On each of three microarray samples, dye swap was performed to correct for dye effects.
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