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Transcriptional regulation of mesencephalic dopaminergic neurons: The full circle of life and death

Interdisciplinary Centre for Neuroscience, Department of Neuroanatomy-Ruprecht-Karls, Universität Heidelberg, Heidelberg, Germany.
Movement Disorders (Impact Factor: 5.68). 02/2008; 23(3):319-28. DOI: 10.1002/mds.21640
Source: PubMed

ABSTRACT Since mesencephalic dopaminergic neurons are associated to one of the most prominent human neurodegenerative ailments, Parkinson's disease, the molecular mechanism underlying their development and adult cellular properties has been the subject of intense investigations. Throughout life, transcription factors determine the fate of this neuronal population and control essential processes such as localization in the ventral midbrain, their neurotransmitter phenotype, their target innervations and synapse formation. Studies of transcription factors, such as Nurr1, Pitx3, Engrailed-1/2, and Lmx1a/b, have not only revealed importance of these genes during development, but also roles in the long-term survival and maintenance of these neurons. In this review, we will discuss the function of these transcription factors throughout the life of mesencephalic dopaminergic neurons and their value in the study of the disease mechanism.

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    • "In recent years, characterization of differential gene expression profiles between the two main mesDA neuronal populations, VTA and SNpc, has been used to probe the question of relative susceptibility of neurons to environmental and genetic vulnerability [7]. Another approach to understand this susceptibility has been the study of the developmental cues that contribute directly or indirectly to differentiation of these phenotypes [8]. "
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    ABSTRACT: Specific vulnerability and degeneration of the dopaminergic neurons in the substantia nigra pars compacta of the midbrain is the pathological hallmark of Parkinson's disease. A number of transcription factors regulate the birth and development of this set of neurons and some remain constitutively expressed throughout life. These maintenance transcription factors are closely associated with essential neurophysiological functions and are required ultimately for the long-term survival of the midbrain dopaminergic neurons. The current review describes the role of two such factors, Nurr1 and engrailed, in differentiation, maturation, and in normal physiological functions including acquisition of neurotransmitter identity. The review will also elucidate the relationship of these factors with life, vulnerability, degeneration and death of mesencephalic dopaminergic neurons in the context of Parkinson's disease.
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    • "Indeed, intermediate genotypes between wild type and double En mutants show varying degrees of VM DA neuronal deficiencies (Sgado et al., 2006; Simon et al., 2001; Sonnier et al., 2007), as has been well-described in recent reviews (Alavian et al., 2008; Alves Dos Santos and Smidt, 2011). The most notable phenotype was observed in En1 (+/−)/En2 (+/+) mutant mice, which display a progressive degeneration (between 8 and 24 weeks) of VM DA neurons that can be antagonised by recombinant En2 protein infusion (Sonnier et al., 2007). "
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    Developmental Biology 04/2013; 379(2). DOI:10.1016/j.ydbio.2013.04.014 · 3.64 Impact Factor
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    • "Bcl-X L effects on maturation are marginal, as discussed later. EN1, LMX1B, NURR1 and PITX3 are not only involved in development, but also in the survival/maintenance of functional A9-DAn ([50] [51] [52] [53] [54] reviewed in [6] [15] [24] [49] [77]). In control hVM1 cells the expression levels of these genes first increase during differentiation (but for PITX3), to later return to values close to basal levels (Fig. 3A and Fig. 5A). "
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