Progressive Loss of Dopaminergic Neurons in the Ventral Midbrain of Adult Mice Heterozygote for Engrailed1

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8542, Development and Evolution of the Nervous System, Group Development and Neuropharmacology, Ecole Normale Supérieure, 75230 Paris Cedex 05, France.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2007; 27(5):1063-71. DOI: 10.1523/JNEUROSCI.4583-06.2007
Source: PubMed


Engrailed1 and Engrailed2 (En1 and En2) are two developmental genes of the homeogene family expressed in the developing midbrain. En1 and, to a lesser degree, En2 also are expressed in the adult substantia nigra (SN) and ventral tegmental area (VTA), two dopaminergic (DA) nuclei of the ventral midbrain. In an effort to study En1/2 adult functions, we have analyzed the phenotype of mice lacking one En1 allele in an En2 wild-type context. We show that in this mutant the number of DA neurons decreases slowly between 8 and 24 weeks after birth to reach a stable 38 and 23% reduction in the SN and VTA, respectively, and that neuronal loss can be antagonized by En2 recombinant protein infusions in the midbrain. These loss and gain of function experiments firmly establish that En1/2 is a true survival factor for DA neurons in vivo. Neuronal death in the mutant is paralleled by a 37% decrease in striatal DA, with no change in serotonin content. Using established protocols, we show that, compared with their wild-type littermates, En1+/- mice have impaired motor skills, an anhedonic-like behavior, and an enhanced resignation phenotype; they perform poorly in social interactions. However, these mice do not differ from their wild-type littermates in anxiety-measuring tests. Together, these results demonstrate that En1/2 genes have important adult physiological functions. They also suggest that mice lacking only one En1 allele could provide a novel model for the study of diseases associated with progressive DA cell death.

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    • "These mice develop PD-like motor symptoms such as reduced locomotor activity (distance travelled, rearing), increased amphetamine-sensitization, and defective motor coordination (rotarod). These mice also present some non-motor phenotypic alterations, such as depressive-like behavior (forced swimming test), anhedonic-like behavior (saccharine preference) and poor social interaction indicating that the moderate loss of mDA neurons in the VTA could affect the mesolimbic system in En1+/À mice [19]. En1 haplodeficient mice thus represent a valuable animal model to gain insight into the mechanisms leading to mDA neuron degeneration in PD. "
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    ABSTRACT: The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms.
    FEBS letters 10/2015; DOI:10.1016/j.febslet.2015.10.002 · 3.17 Impact Factor
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    • "Comparable reads were obtained in WT and En1+/À mice with 989 differentially expressed genes (p < 0.05) (Figure S1A; Table S1). Analysis was performed on 6-week-old animals when all neurons are still present in the in En1+/À mice (Sonnier et al., 2007). Pathway Studio Ontology (gene set enrichment analysis, Pathway Studio software ) indicates that the three most represented and significant groups are DNA repair (p = 0.002), chromatin remodeling (p = 0.004), and transcription factors (p = 0.007); Cell Process Pathways analysis also revealed differential apoptosis regulation genes (p = 0.01) (Figure S1B). "
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    ABSTRACT: Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative stress, and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed1 heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks, and protects dopaminergic neurons against apoptosis.
    Cell Reports 09/2015; 13(2). DOI:10.1016/j.celrep.2015.08.076 · 8.36 Impact Factor
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    • "Similarly, Engrailed survival effect was analyzed for the mesencephalic dopaminergic (mDA) neurons. mDA neurons from the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) that die in Parkinson Disease (PD) express En1 and En2 in the adult and experience progressive mDA cell death in a En1+/- mouse line [62]. As in PD, neuronal death is more accentuated in the SN than in the VTA with 40 and 20% death, respectively, after one year and leads to the motor and non-motor behavior deficits observed in the human disease. "
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    ABSTRACT: The concept of homeoprotein transduction as a novel signaling pathway has dramatically evolved since it was first proposed in 1991. It is now well established in several biological systems from plants to mammals. In this review, the different steps that have led to this unexpected observation are recalled and the developmental and physiological models that have allowed us (and a few others) to consolidate the original hypothesis are described. Because homeoprotein signaling is active in plants and animals it is proposed that it has predated the separation between animals and plants and is thus very ancient. This may explain why the basic phenomenon of homeoprotein transduction is so minimalist, requiring no specific receptors or transduction pathways beside those offered by mitochondria, organelles present in all eukaryotic cells. Indeed complexity has been added in the course of evolution and the conservation of homeoprotein transduction is discussed in the context of its synergy with bona fide signaling mechanism that may have added robustness to this primitive cell communication device. The same synergy possibly explains why homeoprotein signaling is important both in embryonic development and in adult functions fulfilled by signaling entities (e.g. growth factors) themselves active throughout development and in the adult. The cell biological mechanism of homeoprotein transfer is also discussed. Although it is clear that many questions are still in want of precise answers, it appears that the sequences responsible both for secretion and internalization are in the DNA-binding domain and very highly conserved among most homeoproteins. On this basis, it is proposed that this signaling pathway is likely to imply as many as 200 proteins that participate in a myriad of developmental and physiological pathways.
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