Article

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: 5.63). 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.

Download full-text

Full-text

Available from: Horst H Simon, Jul 05, 2015
0 Followers
 · 
104 Views
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the developmental mechanisms governing dopaminergic neuron generation and maintenance is crucial for the development of neuronal replacement therapeutic procedures, like in Parkinson's disease (PD), but also for research aimed at drug screening and pharmacology. In the present chapter, we review the present situation using stem cells of different origins (pluripotent and multipotent) and summarize current manipulations of stem cells for the enhancement of dopaminergic neuron generation, focusing on the actions of Bcl-X(L). Bcl-X(L) not only enhances dopaminergic neuron survival but also augments the expression of key developmental and maintenance genes, and, through the lengthening of the cell cycle early during differentiation, regulates cell fate decisions, producing a net enhancement of neurogenesis. The relevance of these findings is discussed in the context of basic neurogenesis and also for the development of efficient cell therapy in PD.
    Vitamins & Hormones 01/2011; 87:175-205. DOI:10.1016/B978-0-12-386015-6.00029-9