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


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.
    Journal of Biomedical Science 04/2014; 21(1):27. DOI:10.1186/1423-0127-21-27 · 2.76 Impact Factor
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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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    ABSTRACT: Dopaminergic (DA) neurons of the ventral midbrain (VM) play vital roles in the regulation of voluntary movement, emotion and reward. They are divided into the A8, A9 and A10 subgroups. The development of the A9 group of DA neurons is an area of intense investigation to aid the generation of these neurons from stem cell sources for cell transplantation approaches to Parkinson's disease (PD). This review discusses the molecular processes that are involved in the identity, specification, maturation, target innervation and survival of VM DA neurons during development. The complex molecular interactions of a number of genetic pathways are outlined, as well as recent advances in the mechanisms that regulate subset identity within the VM DA neuronal pool. A thorough understanding of the cellular and molecular mechanisms involved in the development of VM DA neurons will greatly facilitate the use of cell replacement therapy for the treatment of PD.
    Developmental Biology 04/2013; 379(2). DOI:10.1016/j.ydbio.2013.04.014 · 3.55 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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    ABSTRACT: Understanding the molecular programs of the generation of human dopaminergic neurons (DAn) from their ventral mesencephalic (VM) precursors is of key importance for basic studies, progress in cell therapy, drug screening and pharmacology in the context of Parkinson's disease. The nature of human DAn precursors in vitro is poorly understood, their properties unstable, and their availability highly limited. Here we present positive evidence that human VM precursors retaining their genuine properties and long-term capacity to generate A9 type Substantia nigra human DAn (hVM1 model cell line) can be propagated in culture. During a one month differentiation, these cells activate all key genes needed to progress from pro-neural and pro-dopaminergic precursors to mature and functional DAn. For the first time, we demonstrate that gene cascades are correctly activated during differentiation, resulting in the generation of mature DAn. These DAn have morphological and functional properties undistinguishable from those generated by VM primary neuronal cultures. In addition, we have found that the forced expression of Bcl-X(L) induces an increase in the expression of key developmental genes (MSX1, NGN2), maintenance of PITX3 expression temporal profile, and also enhances genes involved in DAn long-term function, maintenance and survival (EN1, LMX1B, NURR1 and PITX3). As a result, Bcl-X(L) anticipates and enhances DAn generation.
    Experimental Cell Research 08/2012; 318(19):2446-59. DOI:10.1016/j.yexcr.2012.07.018 · 3.25 Impact Factor
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