Generation of Functional Dopamine Neurons from Neural Precursor Cells Isolated from the Subventricular Zone and White Matter of the Adult Rat Brain Using Nurr1 Overexpression

Shim, Jae Kun; Park, Chang-Hwan; Bae, Yong-Chul; Bae, Jin-Young; Chung, Seungsoo; Chang, Mi-Yoon; H, Koh; Lee, Hyun‐Seob; Hwang, Se Jin; Lee, Ki-Hwan; Lee, Yong-Sung; Choi, Cha-Yong; Lee, Sang-Hun

doi:10.1634/stemcells.2006-0274

Cited by 85 publications

(65 citation statements)

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“…Nurr1 has been reported to act as a transcription factor for expression of tyrosine hydroxylase (Th), the rate-limiting enzyme for DA synthesis (Sakurada et al, 1999). Gain-of-function studies have demonstrated that forced Nurr1 expression induces complete DA phenotype gene expression in naive, non-dopaminergic neural precursor cells (NPCs) (Kim et al, 2003a;Shim et al, 2007;Wagner et al, 1999). Thus, Nurr1 is regarded as the most crucial factor in acquiring the DA phenotype during late mDA neuron development.…”

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confidence: 99%

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Rhee

et al. 2014

Development

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Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-associated disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Coexpression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoRESTHdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.KEY WORDS: Foxa2, Nurr1, Midbrain dopamine neuron, Development, Neural precursor cell, Epigenetic control, CoREST, Hdac, Mouse INTRODUCTIONMidbrain dopamine (mDA) neurons play important roles in voluntary movement, emotion and reward-based behaviors. Dysfunction or degeneration of this neuronal subtype is related to major neuropsychiatric disorders such as Parkinson's disease (PD), schizophrenia and drug addiction. Owing to the pathophysiological implications, mDA neurons are the most extensively studied cells. A molecular understanding of mDA neuron development is of high clinical interest as replacing this cell population in diseased brains is considered to be one of the most promising therapeutic approaches for PD (Deierborg et al., 2008;Morizane et al., 2008). In addition, developmental information can be exploited to establish optimal bioassays for mDA neuron-related disorders. mDA neurons arise from floor plate cells at the ventral midline of the embryonic midbrain (Bonilla et al., 2008;Ono et al., 2007). Sonic hedgehog (Shh), secreted initially by the notochord and later by floor plate cells, induces expression of forkhead family of winged-helix transcription factor 2 (Foxa2; also known as hepatocyte nuclear factor 3 beta), in the midbrain floor plate cells [mouse embryonic day (E) 8.5] (Ang et al., 1993;Monaghan et al., 1993;Placzek, 1995;Sasaki and Hogan, 1994;Sasaki et al., 1997). Foxa2 acts as a master regulator to induce expression of developmental factors specifying mDA neuron precursors such as Nurr1, Pitx3, Lmx1a, Msx1, neurogenin 2 and Mash1 (Ascl1 -Mouse Genome Informatics) (Ang, 2009;Ferri et al., 2007;Kittappa et al., 2007;Lee et al., 2010;Metzakopian et al., 2012). The early inductive role of Foxa2 is probably achieved by cooperation with the Wnt-Lmx1a/b regulatory loop from the isthmic organizer (Chung et al., 2009;Naka...

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Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Rhee

et al. 2014

Development

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“…Dopaminergic neuroblasts for preclinical animal models have been cultured from various different stem cell sources, including ESCs [72][73][74][75][76][77][78][79] , fetal NSCs and precursors of embryonic ventral mesencephalon [80][81][82][83] , adult NSCs from the SVZ [84] , bone marrow stem cells [85] , and fibroblast-derived iPSC cells [86] . Although a small portion of dopaminergic neurons derived from transplanted cells contain disease-specific Lewy bodies 11 to 16 years after transplantation [87,88] , implanted cells remained viable [23,89] .…”

Section: Parkinson's Diseasementioning

confidence: 99%

Adult human neural stem cell therapeutics: Current developmental status and prospect

Nam

Lee

Nam

et al. 2015

WJSC

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Over the past two decades, regenerative therapies using stem cell technologies have been developed for various neurological diseases. Although stem cell therapy is an attractive option to reverse neural tissue damage and to recover neurological deficits, it is still under development so as not to show significant treatment effects in clinical settings. In this review, we discuss the scientific and clinical basics of adult neural stem cells (aNSCs), and their current developmental status as cell therapeutics for neurological disease. Compared with other types of stem cells, aNSCs have clinical advantages, such as limited proliferation, inborn differentiation potential into functional neural cells, and no ethical issues. In spite of the merits of aNSCs, difficulties in the isolation from the normal brain, and in the in vitro expansion, have blocked preclinical and clinical study using aNSCs. However, several groups have recently developed novel techniques to isolate and expand aNSCs from normal adult brains, and showed successful applications of aNSCs to neurological diseases. With new technologies for aNSCs and their clinical strengths, previous hurdles in stem cell therapies for neurological diseases could be overcome, to realize clinically efficacious regenerative stem cell therapeutics.

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“…4) are derived from mouse ES cells, using forced expression of the transcription factor Lmx1a, according to the protocol published by Friling et al [62] in 2009. Other types of stem cells, such as NSCs and progenitors from the embryonic ventral mesencephalon [64][65][66][67], adult NSCs from the subventricular zone [68], bone marrow stromal cells [69], and fibroblast-derived induced pluripotent stem (iPS) cells [61,[70][71][72] have also been used for this purpose. It has also been shown that human stem cell-derived DA neuroblasts, which will be required for patient application, can survive in animal models of PD and after maturation exert functional effects [54,58,66,69,71,72].…”

Section: Can Stem Cell-derived Neurons Replace Fetal Grafts In Pd Patmentioning

confidence: 99%

Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

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The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

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Generation of Functional Dopamine Neurons from Neural Precursor Cells Isolated from the Subventricular Zone and White Matter of the Adult Rat Brain Using Nurr1 Overexpression

Abstract: ABSTRACT

Cited by 85 publications

References 47 publications

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Adult human neural stem cell therapeutics: Current developmental status and prospect

Cell Therapeutics in Parkinson's Disease

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