Paris Science Lettres Research University
Paris Science Lettres Research University
Fuchs J.,The Interdisciplinary Center |
Fuchs J.,University Pierre and Marie Curie |
Fuchs J.,Paris science Lettres Research University |
Stettler O.,University of Paris Descartes |
And 10 more authors.
European Journal of Neuroscience | Year: 2012
Several homeoproteins can function in a direct cell non-autonomous fashion to control various biological processes. In the developing nervous system, this mode of signaling has been well documented for Engrailed in the guidance of retinal ganglion cell axons and retino-tectal patterning. Engrailed is also a key factor for mesencephalic dopaminergic (mDA) neurons, not only during development but also in the adult. Haplodeficiency for Engrailed1 leads to progressive adult-onset loss of mDA neurons and several phenotypic alterations reminiscent of Parkinson's disease (PD). Thanks to its transduction properties, Engrailed has been shown to confer neuroprotection in several experimental models of PD. Study of the mechanisms underlying these two Engrailed-mediated effects has revealed a key role of the translation regulation by Engrailed and uncovered an unsuspected link between a homeoprotein and mitochondrial activity. These studies highlight the crucial role of cellular energetic metabolism in neuron development, survival and neurodegeneration, and may help to identify novel therapeutic targets. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
Alvarez-Fischer D.,University Pierre and Marie Curie |
Alvarez-Fischer D.,The Interdisciplinary Center |
Alvarez-Fischer D.,Groupe Hospitalier Pitie Salpetriere |
Alvarez-Fischer D.,University of Marburg |
And 29 more authors.
Nature Neuroscience | Year: 2011
Mice heterozygous for the homeobox gene Engrailed-1 (En1) display progressive loss of mesencephalic dopaminergic (mDA) neurons. We report that exogenous Engrailed-1 and Engrailed-2 (collectively Engrailed) protect mDA neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I toxin used to model Parkinson's disease in animals. Engrailed enhances the translation of nuclearly encoded mRNAs for two key complex I subunits, Ndufs1 and Ndufs3, and increases complex I activity. Accordingly, in vivo protection against MPTP by Engrailed is antagonized by Ndufs1 small interfering RNA. An association between Engrailed and complex I is further confirmed by the reduced expression of Ndufs1 and Ndufs3 in the substantia nigra pars compacta of En1 heterozygous mice. Engrailed also confers in vivo protection against 6-hydroxydopamine and Î ±-synuclein- A30P. Finally, the unilateral infusion of Engrailed into the midbrain increases striatal dopamine content, resulting in contralateral amphetamine-induced turning. Therefore, Engrailed is both a survival factor for adult mDA neurons and a regulator of their physiological activity. © 2011 Nature America, Inc. All rights reserved.
Walter M.,University Pierre and Marie Curie |
Walter M.,Paris Science Lettres Research University |
Walter M.,French National Center for Scientific Research |
Walter M.,French Institute of Health and Medical Research |
And 13 more authors.
eLife | Year: 2016
DNA methylation is extensively remodeled during mammalian gametogenesis and embryogenesis. Most transposons become hypomethylated, raising the question of their regulation in the absence of DNA methylation. To reproduce a rapid and extensive demethylation, we subjected mouse ES cells to chemically defined hypomethylating culture conditions. Surprisingly, we observed two phases of transposon regulation. After an initial burst of de-repression, various transposon families were efficiently re-silenced. This was accompanied by a reconfiguration of the repressive chromatin landscape: while H3K9me3 was stable, H3K9me2 globally disappeared and H3K27me3 accumulated at transposons. Interestingly, we observed that H3K9me3 and H3K27me3 occupy different transposon families or different territories within the same family, defining three functional categories of adaptive chromatin responses to DNA methylation loss. Our work highlights that H3K9me3 and, most importantly, polycomb-mediated H3K27me3 chromatin pathways can secure the control of a large spectrum of transposons in periods of intense DNA methylation change, ensuring longstanding genome stability. © Walter et al.