Identification and validation of transcription factors and open chromatin regions defining the early postnatal striatal striosome
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ABSTRACT:
PROVIDER: PRJNA599576 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10849600_1.fastq.gz | Fastqsanger.gz | |||
| SRR10849600_2.fastq.gz | Fastqsanger.gz | |||
| SRR10849601_1.fastq.gz | Fastqsanger.gz | |||
| SRR10849601_2.fastq.gz | Fastqsanger.gz | |||
| SRR10849602_1.fastq.gz | Fastqsanger.gz |
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Project description:The basal ganglia, best known for processing information required for initiation of movement, is also part of a network which regulates other aspects of movement, reward, and cognition. The major output nucleus of the basal ganglia is the striatum, and its functions are dependent on neuronal compartmentation, including into striosomes and matrix. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), all of which share basic molecular signatures but are subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating terminal neuronal differentiation following migration are largely unidentified. We performed RNA- and ATAC-seq on sorted murine striosome and matrix cells at postnatal day 3 and with a focus on the striosomal compartment, validated the localization and/or role of transcription factors and their regulator(s), previously not known to be associated with striatal development, including Irx1, Foxf2, Olig2 and Stat1. In addition, we validated the enhancer function of a striosome-specific open chromatin region located 15Kb downstream of the Olig2 gene. These data and the data bases provide novel tools to dissect the networks regulating MSN compartmentation and differentiation and thus pathways relevant to movement and cognition.
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Project description:We recently identified heterozygous deletions of the gene TSHZ3, which encodes a Zn-finger transcription factor, in patients with a syndrome including autistic features and provided evidence in mice for a link between Tshz3 haploinsufficiency, defects in cortical projection neurons (CPNs) and autism spectrum disorder (ASD)-like abnormalities. To get more insight into when and where TSHZ3 is required for the proper development of the brain, we generated and characterized a novel mouse model of conditional Tshz3 deletion in projection neurons from postnatal day 2-3 onward. These mice exhibit altered striatal expression of genes encoding for synaptic components, electrophysiological and synaptic changes in striatal cholinergic interneurons, , as well as ASD-relevant behavioral deficits. These data, by revealing a crucial postnatal role of TSHZ3 in the development and function of the corticostriatal circuitry that might be determinant for ASD pathogenesis, offer a novel ASD model and further open the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.
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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:Parkinsonâs disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Parkinsonâs disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Tissue was dissected from the brain of 6 months old (2 WT / 2 TgA / 2 TgB striata, 2 WT / 2 TgA / 2 TgB brainstems/midbrains, 2 WT / 2 TgA / 2 TgB cerebella) and of 18+ months old mice (4 WT / 2 TgA / 2 TgB striata, 6 WT / 4 TgA / 3 TgB brainstems/midbrains, 6 WT / 5 TgA / 4 TgB cerebella). Tissues from individual, particularly old mice up to 28 months age were included here to strengthen the definition of progression markers reflecting old age.
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Project description:Dysregulation of the striatum is linked to multiple diseases including Huntington’s (HD), Parkinson’s, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neuronal cell type in the striatum and are critical to motor control. The transcription factor Bcl11b (also known as CTIP2) is known to regulate of MSN differentiation, striatal striosome (patch) development and the architecture of the striatum during development. However, the function of Bcl11b adult striatal neurons in vivo has not been investigated. Therefore, we conditionally knocked out Bcl11b specifically in MSNs using D9-cre under the control of a regulatory elements of the mouse Ppp1r1b gene encoding DARPP-32 resulting in knockout around 5-6 weeks of age. Transcriptomic and behavioral analysis were performed on these mice.
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Project description:Postnatal Conditional Knockout of Bcl11b in Striatal Projection Neurons Mimics the Transcriptional Signature of Huntington’s Disease
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Project description:Parkinson’s disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Parkinson’s disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse.
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