Generation of tyrosine hydroxylase-immunoreactive neurons in ventral mesencephalic tissue of Nurr1 deficient mice

Törnqvist, Nina; Hermanson, Elisabet; Perlmann, Thomas; Strömberg, Ingrid

doi:10.1016/s0165-3806(01)00317-0

Cited by 16 publications

(7 citation statements)

References 29 publications

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“…However, defects in neuronal migration, patterning and axonal outgrowth of mdDA neurons in Nurr1 -/-embryos have been reported (Wallen et al, 1999;Tornqvist et al, 2002). The most dramatic aspect of the Nurr1 phenotype is the progressive loss of mdDA neurons during late developmental stages of Nurr1 -/-embryos.…”

Section: Introductionmentioning

confidence: 99%

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

et al. 2009

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The orphan nuclear receptor Nurr1 is essential for the development of meso-diencephalic dopamine (mdDA) neurons and is required, together with the homeobox transcription factor Pitx3, for the expression of genes involved in dopamine metabolism. In order to elucidate the molecular mechanisms that underlie the neuronal deficits in Nurr1 -/-mice, we performed combined gene expression microarrays and ChIP-on-chip analysis and thereby identified Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in vivo. In line with the previously described cooperativity between Nurr1 and Pitx3, we show that the expression of Ptpru and Klhl1 in mdDA neurons is also dependent on Pitx3. Furthermore, we demonstrate that Nurr1 interacts with the Ptpru promoter directly and requires Pitx3 for full expression of Ptpru in mdDA neurons. By contrast, the expression of Dlk1 is maintained in Pitx3 -/-embryos and is even expanded into the rostral part of the mdDA area, suggesting a unique position of Dlk1 in the Nurr1 and Pitx3 transcriptional cascades. Expression analysis in Dlk1 -/-embryos reveals that Dlk1 is required to prevent premature expression of Dat in mdDA neuronal precursors as part of the multifaceted process of mdDA neuronal differentiation driven by Nurr1 and Pitx3. Taken together, the involvement of Nurr1 and Pitx3 in the expression of novel target genes involved in important neuronal processes such as neuronal patterning, axon outgrowth and terminal differentiation, opens up new avenues to study the properties of mdDA neurons during development and in neuronal pathology as observed in Parkinson's disease.

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Section: Introductionmentioning

confidence: 99%

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

et al. 2009

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“…Nurr-1 (NR4A2) is a transcription factor in the orphan nuclear receptor family. Previous studies in cell cultures in vitro have revealed the role of Nurr-1 in differentiation and morphological maturation of dopaminergic neurons (5,12,15,34). In many previous studies, the Nurr-1 gene has been used as a marker for dopaminergic neurons (4,18).…”

Section: Discussionmentioning

confidence: 99%

“…Nurr-1 is a transcription factor, which is essential in the generation, maturation, and migration, as well as differentiation, of midbrain dopaminergic cells (12,15, 34). It has been reported that Nurr-1 plays a critical role in mesencephalic dopaminergic neuronal development in association with the dopamine D2 receptor through the extracellular signal-regulated kinase signaling pathway (14).…”

Section: Introductionmentioning

confidence: 99%

Facilitated Neural Differentiation of Adipose Tissue–Derived Stem Cells by Electrical Stimulation and Nurr-1 Gene Transduction

Yang

et al. 2016

Cell Transplant

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Neuron-like cells derived from adipose tissue-derived stem cells (ADSCs) have been considered one of the most promising cells for the treatment of neurodegenerative diseases and neurotrauma in the central nervous system (CNS). Thus far, extensive efforts have been made to facilitate neuronal differentiation of ADSCs, but limited progress has been achieved. In the present study, we tested the possibility of using a combination of electrical stimulation (ES) with Nurr-1 gene transduction to promote neuronal differentiation of ADSCs. The tolerance of ADSCs to ES was first examined by a cell apoptosis assay. The proliferation of cells was characterized using a CCK-8 assay. The morphology of cells was examined by scanning electron microscopy (SEM). The differentiation of ADSCs into neuron-like cells was examined by immunocytochemistry (ICC)-immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and enzyme linked immunosorbent assay (ELISA). The gene expression of microtubule-associated protein 2 (MAP-2), b-tubulin, neurofilament 200 (NF-200), octamer binding transcription factor 4 (OCT-4), and glial fibrillary acidic protein (GFAP) after stimulation was examined by qRT-PCR. We found that the optimal intensity of ES for neuronal differentiation of ADSCs was 1 V/cm. In addition, ES combined with Nurr-1 gene transduction increased the neuronal differentiation rate of ADSCs, the length of neurite-like processes, and the secretion of dopamine. Further studies showed that a combination of ES with Nurr-1 gene transduction was capable of promoting the expression of MAP-2, b-tubulin, and NF-200 but decreased the expression of OCT-4 and GFAP. All of these findings indicate that a combination of ES with Nurr-1 gene transduction could facilitate neuronal differentiation of ADSCs, which raises the possibility of its application in the treatment of neurodegenerative diseases and neurotrauma in the CNS.

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“…Neuronal differentiation from precursors is enhanced by GDNF, BDNF,100 and natural BMP receptor antagonists 96. Expression of a dopaminergic phenotype can be driven by transcription factors such as Pitx3101 and Nurr1, which drive genes of the full DA neuronal phenotype such as TH, DAT, and components of trophic factor receptors102–104 (see Fig 3). Furthermore, release of GDNF or BDNF by genetically modified cells in the caudate‐putamen can increase survival of precursor cells and of dopaminergic neurons in the lesioned SN,105 and the programmed cell death process also can be temporarily suspended by antiapoptotic factors, for example, XIAP 106.…”

Section: How Can Stem Cell Biology Research Help Parkinson Patients?mentioning

confidence: 99%

Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells

2003

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New therapeutic nonpharmacological methodology in Parkinson's disease (PD) involves cell and synaptic renewal or replacement to restore function of neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell therapy in PD patients and laboratory models, it has been demonstrated that functional motor deficits associated with parkinsonism can be reduced. Similar results have been observed in animal models with stem cell-derived DA neurons. Evidence obtained from transplanted PD patients further shows that the underlying disease process does not destroy transplanted fetal DA cells, although degeneration of the host nigrostriatal system continues. The optimal DA cell regeneration system would reconstitute a normal neuronal network capable of restoring feedback-controlled release of DA in the nigrostriatal system. The success of cell therapy for PD is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra pars compacta as well as the technical and surgical steps associated with the transplantation procedure. Recent laboratory work has focused on using stem cells as a starting point for deriving the optimal DA cells to restore the nigrostriatal system. Ultimately, understanding the cell biological principles necessary for generating functional DA neurons can provide many new avenues for better treatment of patients with PD.

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Generation of tyrosine hydroxylase-immunoreactive neurons in ventral mesencephalic tissue of Nurr1 deficient mice

Cited by 16 publications

References 29 publications

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

Identification ofDlk1, PtpruandKlhl1as novel Nurr1 target genes in meso-diencephalic dopamine neurons

Facilitated Neural Differentiation of Adipose Tissue–Derived Stem Cells by Electrical Stimulation and Nurr-1 Gene Transduction

Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells

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