Etude de l’expression de l'homéoprotéine Engrailed dans l’hippocampe et de ses effets sur la complexité dendritique

Abstract : Engrailed (En) is an important transcription factor in embryo’s segmentation and anterior-posterior axis establishment during early embryogenesis. As several homeoproteins, Engrailed can act as an extracellular signalling molecule which can be internalized by target cells thanks to its penetratin domain and act through transcriptional and/or translation dependent mechanisms. Engrailed has for instance, translation-dependent effects on axonal guidance and cerebral infusion of Engrailed protects dopaminergic neurons in a Parkinson disease model by increasing mitochondrial protein translation. Also, cognitive defects were observed in En1+/+ and En2-/- and En2 expression is increased in ASD patients. This work consisted in extending the knowledge of Engrailed expression and functions. We explored the links with a telencephalic structure where it is a priori fewly expressed (hippocampus). Our results confirm En1 and En2 expression in the mature hippocampus and describe their respective expression along the development of this structure. En1 and En2 have different expression patterns during the first post-natal week as well as in the adulthood suggesting a genetic dosage of Engrailed during the development, specifically with the beginning of synaptogenesis. We also reveal that Engrailed, expressed in hippocampal neurons, is more expressed in GABA-ergic neurons, notably in their dendritic and axonal neurites. We observe that an excess of Engrailed (described in some ASD cases) increases dendritic complexity as well as plastic dendritic spine density, without affecting mature excitatory synapses. We show that En2-/- and heterozygote En1 mice have variations in dendritic spine density, which confirms that Engrailed is involved either in their formation or stabilization. Even though our experiments show no modification of synapse density with an excess of Engrailed, a mutant showing a decreased eIF4E interaction and less efficient than wild type Engrailed to increase dendritic spine density, decreases presynaptic button density and synaptic matching. Those results indicate that eIF4E interaction with Engrailed is, at least in part, responsible for its effects on spinogenesis and suggest a role of Engrailed in presynaptic button formation/stabilization. Key-role of eIF4E in translation allow to hypothesize that some of Engrailed effects we report could be translation dependent. In this sense, our results show that Engrailed is able to increase proteic synthesis in hippocampal neurons. This translation is different from the one induced by chemical LTP (LTPc): it is not altered by synthetic AβO, which are the main toxic agent when produced at abnormally high levels in Alzheimer disease. Engrailed is also able to restore defaulting translation in neurons from Alzheimer disease mice model (TG2576). As a whole, our results identify Engrailed as a novel actor in dendritic plasticity. They reveal that an excess of Engrailed during synaptogenesis can modify dendrite characteristics. This can lead to dendritic network dysfunction in a context of pathologic surexpression of Engrailed. Our observations open to new perspectives contributing to a better understanding of the relationship between Engrailed and ASD. Finally, this work lays the foundation to potentially fruitful links between Engrailed and AβOligomers signalling pathways, where modulation of protein synthesis could be a therapeutic lever in physiopathologic conditions.
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Asma Soltani. Etude de l’expression de l'homéoprotéine Engrailed dans l’hippocampe et de ses effets sur la complexité dendritique. Médecine humaine et pathologie. Université René Descartes - Paris V, 2014. Français. ⟨NNT : 2014PA05T006⟩. ⟨tel-01124327⟩

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