Transcriptomic (RNA-seq) analysis of wild-type and Nolz1-/- (Zfp503) mutant striatal tissue reveals altered expression of several genes involved in striatal projection neuron specification.
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ABSTRACT:
PROVIDER: PRJEB33957 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3476200_1.fastq.gz | Fastqsanger.gz | |||
| ERR3476200_2.fastq.gz | Fastqsanger.gz | |||
| ERR3476195_1.fastq.gz | Fastqsanger.gz | |||
| ERR3476195_2.fastq.gz | Fastqsanger.gz | |||
| ERR3476196_1.fastq.gz | Fastqsanger.gz |
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Project description:Midbrain dopaminergic (DA) axons make long longitudinal projections towards target areas in the forebrain, including the striatum. After demonstrating a striatal specific requirement of transcriptional regulator Nolz1 (Zfp503) in regulating DA axon guidance and innervation, we performed RNA-seq analysis on both wild-type and Nolz1-/- mutant striatal tissue. The gene expression analysis revealed a requirement of Nolz1 in regulating striatal projection neuron specification. The RNA-seq results reveal several secreted factors that underlie the observed guidance defects and resulted in the identification of proteins that can restore DA axonal outgrowth.
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Project description:The molecular mechanisms that underlie striatal development and organization remain largely unknown. Here, we show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates organizational features of striatal circuitry in a cell-type dependent fashion. Using single-cell RNA-sequencing, we examine the cellular diversity of the early postnatal striatum and demonstrate that Foxp1 specifies a subpopulation of indirect pathway spiny projection neurons (iSPNs) while maintaining the striosome-matrix architecture through molecular mechanisms mediated by direct pathway spiny projection neurons (dSPNs). Functionally, Foxp1 alters striatal projection patterns both cell-autonomously and non-autonomously. We connect these changes in striatal circuitry to distinct behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. These data reveal novel cell-type specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development
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Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease. To profile the cell-type-specific responses of striatal spiny projection neurons (SPNs) to striatal dopamine depletion, we conducted TRAP analysis of the two major classes of these neurons: dSPNs that express the dopamine receptor 1a (Drd1a), and iSPNs that express the dopamine receptor 2 (Drd2). To disrupt dopamine innervation to both of these SPN populations that reside in the striatum, we injected the neurotoxin 6-hydroxydopamine (6-OHDA), unilaterally, in the medial forebrain bundle (MFB) in hemizygous Drd1-TRAP and Drd2-TRAP adult (9-14 weeks) male mice (kept on a C57BL/6J genetic background). This lesion procedure causes nigral dopamine cell death within a few days, along with a widespread and near-complete loss of dopaminergic innervation to the entire dorsal striatum on one side of the brain (a hemiparkinsonian model). We first examined the effects of dopamine depletion alone, compared to a mock lesion (ascorbate / saline injected). We then examined the effects of chronic levodopa treatment upon the molecular profiles of dopamine- depleted dSPNs and iSPNs, with two dose regimens. The ‘high-dose’ L-DOPA regimen (3 mg/kg on days 1-3, followed by 6 mg/kg on days 4-9) was expected to induce severe dyskinesia in all MFB-lesioned mice. The low-dose L-DOPA regimen (1 mg/kg on days 1-3, followed by 2 mg/kg on days 4-9) was expected to reverse limb use asymmetry without causing conspicuous dyskinesias. To equalize the effects of stress and handling across all groups, including control groups, all mice were equally handled and thus received saline injections when not receiving levodopa injections. Each treatment group contained 7-10 replicates. TRAP-purified mRNAs from either Drd1a- or Drd2-expressing SPNs were reverse-transcribed, amplified, and used to interrogate Affymetrix 430_2.0 GeneChip microarrays.
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Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.
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Project description:Neuronal DNA modifications differ from those in other cells, including methylation outside CpG context and abundant 5-hydroxymethylation whose relevance for neuronal identities are unclear. Striatal projection neurons expressing D1 or D2 dopamine receptors allow addressing this question, as they share many characteristics but differ in their gene expression profiles, connections, and functional roles. We compare translating mRNAs and DNA modifications in these two populations. DNA methylation differences occur predominantly in large genomic clusters including differentially expressed genes, potentially important for D1 and D2 neurons. Decreased gene body methylation is associated with higher gene expression. Hydroxymethylation differences are more scattered and affect transcription factor binding sites, which can influence gene expression. We also find a strong genome-wide hydroxymethylation asymmetry between the two DNA strands, particularly pronounced at expressed genes and retrotransposons. These results identify novel properties of neuronal DNA modifications and unveil epigenetic characteristics of striatal projection neurons heterogeneity.
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Project description:Transcriptomic (RNA-seq) analysis of wild-type and Nolz1-/- (Zfp503) mutant striatal tissue reveals altered expression of several genes involved in striatal projection neuron specification.
2019-09-09 | E-MTAB-8240 | ExpressionAtlas
Project description:Cortical projection neurons comprise classes of neurons connecting the cerebral cortex to distant targets in the nervous system. Each projection neuron class acquires a distinct molecular identity and develops characteristic patterns of axonal projection and dendritic arborization that determine their inputs, outputs, and distinct functions. How different aspects of neuron identity, including axonal and dendritic morphology, are coordinated appropriately in each specific neuron type is not known. A network of transcription factors, including the selector gene Fezf2, is central to specifying cortical projection neuron fates. However, regulation down-stream of these fate-determinant transcription factors to control different aspects of neuron identity is not understood, particularly as it relates to the development of distinct dendritic arbors that determine the inputs to each projection neuron class. Here we show that the miR-193b~365 microRNA cluster downstream of Fezf2 cooperatively represses the signaling molecule Mapk8 to regulate dendritic development in a neuron subtype-specific manner.
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