Specificity of Pitx3-Dependent Gene Regulatory Networks in Subsets of Midbrain Dopamine Neurons
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE93275 | GEO | 2017/01/07
SECONDARY ACCESSION(S): PRJNA360450
REPOSITORIES: GEO
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: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: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.
2011-11-22 | GSE32940 | GEO
Project description:Midbrain dopamine (mDA) neurons play critical roles in the regulation of voluntary movement and their dysfunction is associated with Parkinson's disease. Pitx3 has been implicated in the proper development of mDA neurons in the substantia nigra pars compacta, which are selectively lost in Parkinson's disease. However, the basic mechanisms underlying its role in mDA neuron development and/or survival are poorly understood. Toward this goal, we sought to identify downstream target genes of Pitx3 by comparing gene expression profiles in mDA neurons of wild-type and Pitx3-deficient aphakia mice. This global gene expression analysis revealed many potential target genes of Pitx3; in particular, the expression of vesicular monoamine transporter 2 and dopamine transporter, responsible for dopamine storage and reuptake, respectively, is greatly reduced in mDA neurons by Pitx3 ablation. In addition, gain-of-function analyses and chromatin immunoprecipitation strongly indicate that Pitx3 may directly activate transcription of vesicular monoamine transporter 2 and dopamine transporter genes, critically contributing to neurotransmission and/or survival of mDA neurons. As the two genes have been known to be regulated by Nurr1, another key dopaminergic transcription factor, we propose that Pitx3 and Nurr1 may coordinately regulate mDA specification and survival, at least in part, through a merging and overlapping downstream pathway.
| S-EPMC4896488 | biostudies-literature
Project description:RNAseq analysis on E14.5 midbrain material from mouse, Lmx1b fl/fl; Pitx3-Cre vs Lmx1v wt/wt;Pitx3-Cre littermates
| PRJNA495800 | ENA
Project description:A new mouse mutant arose spontaneously at the 5th inbred generation in a congenic C3H/He line. Since the mice suffered from anophthalmia or microphthalmia, we referred to this new mutant as eyeless (provisional gene symbol: eyl). The mutation follows an autosomal recessive pattern of inheritance and was mapped to chromosome 19 close to Pitx3; complementation tests confirmed that eyl is an allelic variant of aphakia (gene symbol: ak). Sequence analysis of the Pitx3 gene identified an insertion of a G in exon 4 (after cDNA position 416: 416insG). The altered open reading frame is predicted to result in a hybrid protein still containing the Pitx3 homeobox, but 121 new amino acids instead of the OAR domain at its C-terminal part. The new Pitx3eyl allele shares the ophthalmological and brain defects of the aphakia mouse including the loss of dopamine transporter 1 transcripts in the midbrain. Moreover, we observed in the mutants an increased extramedullary hematopoiesis in the spleen, and frequently also hepatosteatosis, combined with a reduced body weight. Fat mass, fat content and subcutaneous fat are significantly decreased in females, but not in males. Additionally, we observed a broad spectrum of behavioural changes in the homozygous mutants including reduced forelimb grip strength and increased nociception. In addition to these alterations being apparent in both sexes, we observed in female Pitx3eyl-/- mice increased anxiety, reduced locomotor activity, reduced object exploration and increased social contacts, but decreased anxiety and increased arousal in males. Most of these defects identified in the new Pitx3 mutation can also be observed in Parkinson patients. Therefore, the Pitx3eyl mutant is a valuable new model, because it is the first mutant mouse line carrying a point mutation within the coding region of the Pitx3 gene. 5 male animals, 5 experiments including 2 dye swap hybridisations
2010-05-19 | E-GEOD-15336 | biostudies-arrayexpress
Project description:A new mouse mutant arose spontaneously at the 5th inbred generation in a congenic C3H/He line. Since the mice suffered from anophthalmia or microphthalmia, we referred to this new mutant as eyeless (provisional gene symbol: eyl). The mutation follows an autosomal recessive pattern of inheritance and was mapped to chromosome 19 close to Pitx3; complementation tests confirmed that eyl is an allelic variant of aphakia (gene symbol: ak). Sequence analysis of the Pitx3 gene identified an insertion of a G in exon 4 (after cDNA position 416: 416insG). The altered open reading frame is predicted to result in a hybrid protein still containing the Pitx3 homeobox, but 121 new amino acids instead of the OAR domain at its C-terminal part. The new Pitx3eyl allele shares the ophthalmological and brain defects of the aphakia mouse including the loss of dopamine transporter 1 transcripts in the midbrain. Moreover, we observed in the mutants an increased extramedullary hematopoiesis in the spleen, and frequently also hepatosteatosis, combined with a reduced body weight. Fat mass, fat content and subcutaneous fat are significantly decreased in females, but not in males. Additionally, we observed a broad spectrum of behavioural changes in the homozygous mutants including reduced forelimb grip strength and increased nociception. In addition to these alterations being apparent in both sexes, we observed in female Pitx3eyl-/- mice increased anxiety, reduced locomotor activity, reduced object exploration and increased social contacts, but decreased anxiety and increased arousal in males. Most of these defects identified in the new Pitx3 mutation can also be observed in Parkinson patients. Therefore, the Pitx3eyl mutant is a valuable new model, because it is the first mutant mouse line carrying a point mutation within the coding region of the Pitx3 gene.
2009-12-01 | GSE15336 | GEO
Project description:Midbrain dopamine (mDA) neurons constitute a heterogenous group of cells that have been intensely studied, not least because mDA neuron degeneration causes major symptoms in Parkinson’s disease. Diversity of mDA neurons has previously been well characterized anatomically but understanding diversity at a more complete molecular level has not previously been achieved. Here, we used single cell RNA sequencing of isolated mouse neurons expressing the transcription factor Pitx3, a marker for all types of mDA neurons. Analyses included cells isolated during development up until adulthood and was validated by histological characterization of newly identified markers. This characterization identified seven neuron subgroups divided in two major branches of developing Pitx3-expressing neurons. Five of these groups were dopaminergic, one glutamatergic and one GABAergic. Analyses also indicated evolutionary conservation of diversity in humans. This comprehensive molecular characterization will provide a molecular framework for further studies of the developing and mature mDA neuron subgroups in the mammalian brain.
2019-02-08 | GSE116138 | GEO
Project description:single-cell RNA sequencing data (plate-based CelSeq2) of developing mouse ventral midbrain GABAergic neurons. vmbGABA series contains E16 and P0 VGAT mouse ventral midbrain and E16 and P0 VGAT/PITX3 co-expressing mouse ventral midbrain.
2024-10-08 | GSE268378 | GEO
Project description:Midbrain dopamine (DA) neurons play a central role in the regulation of voluntary movement, and their degeneration is associated with Parkinson's disease. Cell replacement therapies, and in particular embryonic stem (ES) cell-derived DA neurons, offer a potential therapeutic venue for Parkinson's disease. We sought to identify genes that can potentiate maturation of ES cell cultures to the midbrain DA neuron phenotype. A number of transcription factors have been implicated in the development of midbrain DA neurons by expression analyses and loss-of-function knockout mouse studies, including Nurr1, Pitx3, Lmx1b, Engrailed-1, and Engrailed-2. However, none of these factors appear sufficient alone to induce the mature midbrain DA neuron phenotype in ES cell cultures in vitro, suggesting a more complex regulatory network. Here we show that Nurr1 and Pitx3 cooperatively promote terminal maturation to the midbrain DA neuron phenotype in murine and human ES cell cultures.
| S-EPMC1413837 | biostudies-other