The fully linked HTML version of this article has now been published.
Development ePress online publication date 2 Jun 2004
doi: 10.1242/dev.01128
Research article: Development and disease
Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons
Lavinia Albéri,
Paola Sgadò,
and
Horst H. Simon*
* Author for correspondence (e-mail: horst.simon{at}urz.uni-heidelberg.de)
The neuropathological hallmark of Parkinson's disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, presumably mediated by apoptosis. The homeobox transcription factors engrailed 1 and engrailed 2 are expressed by this neuronal population from early in development to adulthood. Despite a large mid-hindbrain deletion in double mutants null for both genes, mesencephalic dopaminergic (mDA) neurons are induced, become postmitotic and acquire their neurotransmitter phenotype. However, at birth, no mDA neurons are left. We show that the entire population of these neurons is lost by E14 in the mutant animals, earlier than in any other described genetic model system for Parkinson's disease. This disappearance is caused by apoptosis revealed by the presence of activated caspase 3 in the dying tyrosine hydroxylase-positive mutant cells. Furthermore, using in vitro cell mixing experiments and RNA interference on primary cell culture of ventral midbrain we were able to show that the demise of mDA neurons in the mutant mice is due to a cell-autonomously requirement of the engrailed genes and not a result of the missing mid-hindbrain tissue. Gene silencing in the postmitotic neurons by RNA interference activates caspase 3 and induces apoptosis in less than 24 hours. This rapid induction of cell death in mDA neurons suggests that the engrailed genes participate directly in the regulation of apoptosis, a proposed mechanism for Parkinson's disease.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
Weidong Le, Shen Chen, and J. Jankovic
Etiopathogenesis of Parkinson Disease: A New Beginning?
Neuroscientist,
February 1, 2009;
15(1):
28 - 35.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. Sanchez-Pernaute, H. Lee, M. Patterson, C. Reske-Nielsen, T. Yoshizaki, K. C. Sonntag, L. Studer, and O. Isacson
Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson's disease
Brain,
August 1, 2008;
131(8):
2127 - 2139.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. L. M. Ferri, W. Lin, Y. E. Mavromatakis, J. C. Wang, H. Sasaki, J. A. Whitsett, and S.-L. Ang
Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner
Development,
August 1, 2007;
134(15):
2761 - 2769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Gherbassi, L. Bhatt, S. Thuret, and H. H. Simon
Merging Mouse Transcriptome Analyses with Parkinson's Disease Linkage Studies
DNA Res,
May 23, 2007;
(2007)
dsm007v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Sonnier, G. Le Pen, A. Hartmann, J.-C. Bizot, F. Trovero, M.-O. Krebs, and A. Prochiantz
Progressive Loss of Dopaminergic Neurons in the Ventral Midbrain of Adult Mice Heterozygote for Engrailed1
J. Neurosci.,
January 31, 2007;
27(5):
1063 - 1071.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Sgado, L. Alberi, D. Gherbassi, S. L. Galasso, G. M. J. Ramakers, K. N. Alavian, M. P. Smidt, R. H. Dyck, and H. H. Simon
Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice
PNAS,
October 10, 2006;
103(41):
15242 - 15247.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-L. Ang
Transcriptional control of midbrain dopaminergic neuron development
Development,
September 15, 2006;
133(18):
3499 - 3506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Martinat, J.-J. Bacci, T. Leete, J. Kim, W. B. Vanti, A. H. Newman, J. H. Cha, U. Gether, H. Wang, and A. Abeliovich
Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype
PNAS,
February 21, 2006;
103(8):
2874 - 2879.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Prakash, C. Brodski, T. Naserke, E. Puelles, R. Gogoi, A. Hall, M. Panhuysen, D. Echevarria, L. Sussel, D. M. V. Weisenhorn, et al.
A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo
Development,
January 1, 2006;
133(1):
89 - 98.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Miller and H. J. Federoff
Altered Gene Expression Profiles Reveal Similarities and Differences Between Parkinson Disease and Model Systems
Neuroscientist,
December 1, 2005;
11(6):
539 - 549.
[Abstract]
[PDF]
|
|
|
|
|
|
|
N. Offner, N. Duval, M. Jamrich, and B. Durand
The pro-apoptotic activity of a vertebrate Bar-like homeobox gene plays a key role in patterning the Xenopus neural plate by limiting the number of chordin- and shh-expressing cells
Development,
April 15, 2005;
132(8):
1807 - 1818.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Quintanilla, F. J. Munoz, M. J. Metcalfe, M. Hitschfeld, G. Olivares, J. A. Godoy, and N. C. Inestrosa
Trolox and 17{beta}-Estradiol Protect against Amyloid {beta}-Peptide Neurotoxicity by a Mechanism That Involves Modulation of the Wnt Signaling Pathway
J. Biol. Chem.,
March 25, 2005;
280(12):
11615 - 11625.
[Abstract]
[Full Text]
[PDF]
|
|
|
© The Company of Biologists Ltd 2004
