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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Available from: Gwenaëlle Le Pen, Oct 13, 2015
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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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    • "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). The progressive degeneration of VM DA neurons in En1 heterozygotes (En2 null background in Sgado et al. (2006) study) is more pronounced in the SNc and results in reduced striatal DA and motor deficits, as is characteristic of PD pathology (Sgado et al., 2006; Sonnier et al., 2007). These findings further support the theory that En1/En2 function as important survival-promoting factors for VM DA neurons. "
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    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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