Mus musculus
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ABSTRACT:
PROVIDER: PRJNA305311 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Pitx3 is a transcription factor that is expressed in all midbrain dopaminergic (mDA) neurons during early development, but later becomes restricted in dopaminergic subsets of substantia nigra compacta (SNc) and of the ventral tegmental are (VTA) that are vulnerable to neurodegenerative stress (MPTP, 6-OHDA, rotenone, Parkinson's disease). Overall, in mice, Pitx3 is required for developmental survival of ventral SNc neurons and for postnatal survival of VTA neurons (after postnatal day 40). With the aim of determining the gene networks that distinguish Pitx3-vulnerable (Pitx3-positive) from Pitx3-resistant (Pitx3-negative) subsets of SNc and VTA, we performed a comparison at the transcriptome level between FAC-sorted mDA neurons of SNc and VTA that were obtained from wild-type and Pitx3-/- newborn mice. The latter mice have already lost the majority of their TH+Calb1- mDA neurons of ventral SNc (Pitx3-dependent), but their TH+Calb1+ neurons of dorsal SNc (Pitx3-independent), including all of VTA neurons (50% are Pitx3-dependent and 50% Pitx3-independent), are unaffected by Pitx3 deletion. At postnatal day 40, Pitx3-/- mice display a marked loss of dopaminergic subsets of VTA that normally co-express Pitx3 and Calb1 (Pitx3-dependent neurons of VTA).
2016-01-31 | GSE75777 | GEO
Project description:Dopaminergic neurons located in the ventral midbrain can be broadly subdivided into two distinct subpopulations. Substantia nigra (SN) dopaminergic neurons are highly sensitive to toxic insults and selectively degenerate in Parkinson’s disease, while ventral tegmental area (VTA) dopaminergic neurons are associated with other neurological disorders. Access to enriched cultures of SN and VTA dopaminergic neuronal subpopulations will facilitate disease modelling and give insight in the differential vulnerability, but it is unclear how the differentiation of human ES cells can be directed towards these distinct lineages. We found that overexpression of the lineage specifying transcription factors Sox6 and Otx2 can direct the differentiation of human ES cells into enriched populations of respectively SN or VTA neurons. Proteomic analysis of these cultures resulted in the identification of several differential expressed proteins and provided insight in pathways contributing to the selective vulnerability of SN.
2021-11-03 | PXD028639 | Pride
Project description:RNA-SEQ profiling of dopaminergic neurons from the substantia nigra pars compacta and ventral tegmental area regions of the mouse mid-brain Murine midbrain dopaminergic neurons from the SNpc and VTA regions
2015-07-27 | E-GEOD-64452 | biostudies-arrayexpress
Project description:The cardinal clinical features of Parkinson's disease result from selective loss of midbrain dopaminergic neurons. The goal of this experiment is to determine the gene expression profiles of these neurons by studying untreated rat substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopaminergic neurons using laser capture microscopy to obtain region-specific neuronal mRNA.
2007-10-27 | E-GEOD-1157 | biostudies-arrayexpress
Project description:Development of meso-diencephalic dopamine (mdDA) neurons requires the combined actions of the orphan nuclear receptor Nurr1 and the paired-like homeobox transcription factor Pitx3. Whereas all mdDA neurons require Nurr1 for expression of Th and survival, dependence on Pitx3 is only displayed by the mdDA subpopulation that will form the substantia nigra (SNc). Previously, we demonstrated that Pitx3-/- embryos lack the expression of the retinoic acid (RA)-generating enzyme Ahd2, which is normally selectively expressed in the Pitx3-dependent DA neurons of the SNc. Restoring RA-signaling in Pitx3-/- embryos revealed a selective dependence of SNc neurons on the presence of RA for differentiation into Th-positive neurons and maintenance throughout embryonic development. Whereas these data are suggestive of an important developmental role for RA in neurons of the SNc, it remained unclear whether other Nurr1 and Pitx3 target genes depend on RA signaling in a manner similar to Th. In search for genes that were affected in Pitx3-deficient mdDA neurons and restored upon embryonic RA treatment, we provide evidence that Delta-like 1, D2R (Drd2) and TH are regulated by Pitx3 and RA signaling, influencing the mdDA terminal differentiated phenotype. Furthermore, we show that regulation of Ahd2-mediated RA-signaling represents only one aspect of the Pitx3 downstream cascade, since Vmat2, Dat, Ahd2 (Aldh1a1), En1, En2 and Cck were unaffected by RA treatment and are (subset) specifically modulated by Pitx3. In conclusion, our data reveal several RA-dependent and -independent aspects of the Pitx3-regulated gene cascade suggesting that Pitx3 acts on multiple levels in the molecular subset-specification of mdDA neurons. RNA was isolated from dissected ventral midbrains of E14.5 Pitx3-/- and Pitx3+/+ mouse embryos. 3 Experimental samples each consisting of 3 Pitx3-/- ventral midbrains were hybridized to reference RNA derived from 10 Pitx3+/+ ventral midbrains
2011-11-22 | E-GEOD-32940 | biostudies-arrayexpress
Project description:The cardinal clinical features of Parkinson's disease result from selective loss of midbrain dopaminergic neurons. The goal of this experiment is to determine the gene expression profiles of these neurons by studying untreated rat substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopaminergic neurons using laser capture microscopy to obtain region-specific neuronal mRNA. WARNING: These data are identical to those represented in GEO Series GSE1837.
2004-03-29 | GSE1157 | GEO
Project description:FJ001: Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons
| PRJNA146577 | ENA
Project description:The cardinal clinical features of Parkinson's disease (PD) (rigidity, rest tremor, bradykinesia, and postural instability) result from selective loss of midbrain dopaminergic neurons. More specifically, dopaminergic neurons in the substantia nigra pars compacta (SNc) are much more susceptible to damage than the adjacent dopaminergic neurons in the ventral tegmental area (VTA). This dichotomy is not only seen in human Parkinson's disease, but also in many animal models of PD, including administration of the mitochondrial toxin rotenone to rats, which replicates many of the behavioral and neuropathological features of PD. The factors underlying this selective vulnerability are unknown, but could be related to differences in neuronal circuitry, differences in glial support, or intrinsic differences between the neuronal populations of the two regions. Elucidation of these factors may lead to a greater understanding of the pathogenesis and treatment of Parkinson's disease. We will determine gene expression profiles of untreated rat SNc and VTA dopaminergic neurons using laser capture microscopy to obtain region-specific neuronal mRNA. There are intrinsic differences in gene expression between dopaminergic neurons in the rat SNc and VTA that result in greater susceptibility of SNc neurons to degeneration in experimental parkinsonism. These differences may be related to dopamine metabolism, oxidative metabolism and stress, protein aggregation, or other unforseen pathways. We will compare gene expression profiles between SNc and VTA dopaminergic neurons in normal rats. No treatment or time points will be studied in this experiment. Animals will be anesthetized, sacrificed by decapitation, and brains frozen on dry ice. Frozen sections will be collected onto glass microscope slides and rapidly immunostained for tyrosine hydroxylase to identify dopaminergic neurons. SNc and VTA neurons (approx. 200 per sample) will be isolated using laser capture microscopy. Total RNA will be extracted and poly-A RNA will be amplified using a modified Eberwine protocol. aRNA will be sent to the centers for labeling and hybridization to Affymetrix rat U34A arrays. We have confirmed with the center that our aRNA protocol is compatible with the centers amplification protocols; in fact, it is essentially identical. We will be providing a two-round amplification product to the center for labeling and hybridization. We recognize that using RNA after three rounds of amplification may decrease sensitivity for low copy number transcripts, but favor this approach versus pooling our samples (which are inherently paired) at this point. We have discussed this point in detail with the center. SNc and VTA samples from eight animals (16 samples total) will be provided to mitigate differences specific to individual animals. With the assisatnce of the center, paired t-tests will be used to determine differential expression between the two regions. Permutational t-test analysis and/or Benjamini and Hochberg analysis of expression ratios will be used to protect against multiple comparisons. Selected differentially expressed genes will be validated on separate tissue samples using quantitative RT-PCR or in situ hybridization.
2007-09-13 | E-GEOD-1837 | biostudies-arrayexpress
Project description:The development of the mesodiencephalic dopaminergic (mdDA) neurons strongly depends on the WNT1/b-catenin signaling pathway. These neurons include the Substantia nigra pars compacta (SNc) subset that preferentially degenerates in Parkinson’s Disease (PD), and the ventral tegmental area (VTA) subpopulation implicated in a variety of neuropsychiatric disorders. The identity of the cells responding to this signaling pathway in the developing mammalian ventral midbrain (VM) and the precise mechanism of WNT/b-catenin action in these cells, however, are still unknown. Moreover, this signaling pathway has to be accurately balanced during mdDA neuron development: whereas low levels or absence of WNT1/b-catenin signaling abolish their correct specification, constitutive activation of this signaling pathway prevents their proper differentiation in the mouse. We show that the WNT/b-catenin-responsive cells constitute only a fraction of all mdDA progenitors, precursors and neurons in the murine VM. These WNT/b-catenin-responsive cells are mostly located in the Wnt1+, Rspo2+ and Lef1+ lateral floor plate of the medial and caudal midbrain, giving preferentially rise to caudomedial (VTA) mdDA neurons. Strong WNT/b-catenin signaling mediated by RSPO2, a WNT/b-catenin agonist, and LEF1, a nuclear effector of this pathway, inhibits the differentiation of WNT/b-catenin-responsive mdDA progenitors into mature mdDA neurons by repressing the murine Pitx3 gene via conserved LEF1/TCF binding sites in its promoter. Our data indicate that an attenuation of WNT/b-catenin signaling in mdDA progenitors is essential for their correct differentiation into specific mdDA neuron subsets, thus providing a new means for stem cell-based regenerative therapies of PD and in vitro models of neuropsychiatric diseases.
2020-09-02 | GSE99618 | GEO
Project description:WNT1/beta-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons including the Substantia nigra pars compacta (SNc) subpopulation, whose degeneration is a hallmark of Parkinson’s Disease (PD). However, the precise functions of WNT/beta-catenin signaling in this context remain unknown. Using mutant mice, primary ventral midbrain (VM) cells and pluripotent stem cells (mouse embryonic stem cells and induced pluripotent stem cells), we show that Dickkopf 3 (DKK3), a secreted glycoprotein that modulates WNT/beta-catenin signaling, is specifically required for the correct differentiation of a rostrolateral mdDA precursor subset into SNc DA neurons. Dkk3 transcription in the murine VM coincides with the onset of mdDA neurogenesis and is required for the maintenance of LMX1A and consequently PITX3 expression in rostrolateral mdDA precursors, without affecting the proliferation or specification of their progenitors. Treatment of primary VM cells or differentiating pluripotent stem cells with recombinant WNT1 and/or DKK3 proteins consistently increases the proportion of mdDA cells with SNc DA neuron identity and promotes their survival in vitro. The SNc DA pro-differentiation and pro-survival properties of DKK3, together with its known anti-tumorigenic effect, therefore make it an ideal candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. We performed gene expression microarray analysis on iPSC-derived and FACS-sorted GFP-positive Pitx3GFP/+ mdDA neurons, differentiated in the presence or absence of recombinant human WNT1 and recombinant human DKK3. In addition, we analysed primary and FACS-sorted GFP-positive Pitx3+/GFP mdDA neurons isolated from the E13.5 and E14.5 ventral midbrain of Pitx3+/GFP embryos
2015-08-22 | E-GEOD-58813 | biostudies-arrayexpress