Régulation par l’activité glycinergique des mécanismes cellulaires et moléculaires durant la neurogenèse embryonnaire
In the adult central nervous system, glycine is mainly known as an inhibitory neurotransmitter in mature neurons, thereby regulating the neural network activity. Paradoxically, during embryogenesis, the same neurotransmitter generates excitatory transmission and induces the first electrical signal in immature neurons. The role and functional significance of this change in glycinergic activity during neurogenesis are still unknown. In this study, we used zebrafish embryos as a model to explore the glycine-dependent molecular and cellular mechanisms in neural stem cells (NSCs).  First, we developed an in vivo analysis method based on two main elements: a transgenic line that expresses GFP within NSCs and the RNA sequencing technique. This method of analysis was used to determine glycine-dependent molecular mechanisms in NSCs. We identified several candidate genes whose expression is modulated by the glycinergic activity. These genes participate in five different canonical signaling pathways including the calcium signaling pathway, TGF-beta, Shh, Wnt and p53. To further understand these molecular mechanisms, we focused our investigation on the regulation of p53 signaling by the glycinergic activity. Indeed, we have demonstrated that glycinergic activity promotes the survival of NSCs by regulating p53 signaling and more specifically acting on NSC-nestin + subpopulation during neurogenesis. Finally, we explored the regulation of lnx1 expression by glycinergic activity. We have demonstrated that glycine/lnx1 signaling regulates the proliferation of NSCs via the modulation of Notch activity during neurogenesis. In conclusion, during this thesis project, I highlighted several molecular and cellular mechanisms modulated by the glycinergic activity in NSCs. These relevant results may contribute in the future to the understanding of the physiopathology related to glycinergic activity dysfunctions and the identification of new therapeutic targets.
Glycine Cellules souches neurales p53 lnx1 Zebrafish Neurogenesis NSCs Notch signaling