Abstract
NURR1 is an essential transcription factor for the differentiation, maturation, and maintenance of midbrain dopaminergic neurons (DA neurons) as it has been demonstrated using knock-out mice. DA neurons of the substantia nigra pars compacta degenerate in Parkinson’s disease (PD) and mutations in the Nurr1 gene have been associated with this human disease. Thus, the study of NURR1 actions in vivo is fundamental to understand the mechanisms of neuron generation and degeneration in the dopaminergic system. Here, we present and discuss findings indicating that NURR1 is a valuable molecular tool for the in vitro generation of DA neurons which could be used for modeling and studying PD in cell culture and in transplantation approaches. Transduction of Nurr1 alone or in combination with other transcription factors such as Foxa2, Ngn2, Ascl1, and Pitx3, induces the generation of DA neurons, which upon transplantation have the capacity to survive and restore motor behavior in animal models of PD. We show that the survival of transplanted neurons is increased when the Nurr1-transduced olfactory bulb stem cells are treated with GDNF. The use of these and other factors with the induced pluripotent stem cell (iPSC)-based technology or the direct reprogramming of astrocytes or fibroblasts into human DA neurons has produced encouraging results for the study of the cellular and molecular mechanisms of neurodegeneration in PD and for the search of new treatments for this disease.
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Abbreviations
- AADC:
-
L-aromatic amino acid decarboxylase
- ALDH2:
-
Aldehyde dehydrogenase 2
- ALDH1A1:
-
Aldehyde dehydrogenase 1 family member A1
- ASCL1:
-
Achaete-scute complex homolog 1
- BDNF:
-
Brain-derived neurotrophic factor
- bHLH:
-
Basic helix-loop-helix
- CA:
-
Catecholamine
- CNS:
-
Central nervous system
- D1R:
-
Dopamine 1 class receptor
- D2R:
-
Dopamine 2 class receptor
- DA neurons:
-
Dopaminergic neurons
- DAT:
-
Dopamine transporter
- EN:
-
Engrailed genes
- ESCs:
-
Embryonic stem cells
- FGF8:
-
Fibroblast growth factor family member 8
- Fgfr2:
-
Fibroblast growth factor receptor 2
- FOXA2:
-
Forkhead box protein A2
- FP:
-
Floor plate
- GABA:
-
Gamma-aminobutyric acid
- GAD:
-
Glutamic acid decarboxylase
- GDNF:
-
Glial cell line-derived neurotrophic factor
- GIRK2:
-
G-protein-regulated inward-rectifier potassium channel 2
- hiPSCs:
-
Human iPSCs
- iDA neurons:
-
Induced DA neurons
- iNeurons:
-
Induced neurons
- iPSCs:
-
Induced pluripotent stem cells
- LGE:
-
Lateral ganglionic eminence
- mesDA neurons:
-
Mesencephalic DA neurons/midbrain DA neurons
- MHB:
-
Mid-/hindbrain boundary
- MSX1:
-
Msh homeobox 1
- NA:
-
Noradrenaline
- NBRE:
-
NGFI-B response element
- NGN2:
-
Neurogenin 2
- NPCs:
-
Neural progenitor cells
- NR4A:
-
Orphan nuclear receptor family 4
- NSCs:
-
Neural stem cells
- OB:
-
Olfactory bulb
- OBSCs:
-
Olfactory bulb stem cells
- PD:
-
Parkinson’s disease
- PITX3:
-
Pituitary homeobox 3
- PGNs:
-
Periglomerular neurons
- RXR:
-
Retinoid X receptor
- SHH:
-
Sonic hedgehog
- SN:
-
Substantia nigra
- SNc:
-
Substantia nigra pars compacta
- SV2:
-
Synaptic vesicle protein 2
- SVZ:
-
Subventricular zone
- TFs:
-
Transcription factors
- TH:
-
Tyrosine hydroxylase
- TYRP1:
-
Tyrosine-related protein1
- VGAT:
-
Vesicular GABA transporter
- VMAT2:
-
Vesicular monoamine transporter 2
- VTA:
-
Ventral tegmental area
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Acknowledgments
This work was supported by grants from the Spanish Ministerio de Economía y Competitividad (MINECO: BFU2010-1963 and SAF2013-47596-R to C.V.-A. and BFU2010-20664 and SAF2013-48532-R to R.M.), Ministerio de Sanidad, Política Social e Igualdad (Instituto de Salud Carlos III, ISCIII: CIBERNED CB06/05/065 to C.V.-A. and CIBERNED CB06/05/0055 to R.M) and the Comunidad de Madrid (CM: S2011/BMD-2336 to RM and C.V.-A.). O.S., and E.R.-T received fellowships from the CM, CONACYT (Gobierno de Mexico), and MINECO.
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Rosario Moratalla and Carlos Vicario-Abejón are co-senior authors.
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Rodríguez-Traver, E., Solís, O., Díaz-Guerra, E. et al. Role of Nurr1 in the Generation and Differentiation of Dopaminergic Neurons from Stem Cells. Neurotox Res 30, 14–31 (2016). https://doi.org/10.1007/s12640-015-9586-0
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DOI: https://doi.org/10.1007/s12640-015-9586-0