OLGA

Many neurological diseases may benefit from replacement of glial cells (e.g. Multiple Sclerosis, Leukomalacia) or neurons (e.g. Parkinson, Alzheimer) or both (stroke). Replacement could be achieved by stimulating neural stem cells (NSC) to favour endogenous repair. Yet our understanding of how neurons and glial cells are generated during development and in the adult is still insufficient to move forward to therapeutic goals. The molecular mechanisms underlying the glial versus neuronal early fate choice of progenitors are largely unknown, particularly in the mature brain. Thyroid hormone (TH) is a key inductor of neurogenesis as well as myelin synthesis by oligodendrocytes. It is therefore unclear how TH can orient cell fate decision towards one or the other direction. Taking advantage of newly developed in vivo experimental approaches, we have acquired better knowledge of the adult NSC niche and data highlighting the roles of TH in orienting NSC towards a neuronal or oligodendroglial fate. Without bringing into question the large body of data on TH enhancement of (re)myelination in many models, we have obtained novel data on early stages of oligodendrocyte determination. A solid series of unpublished results shows that, at the early progenitor level, oligodendrocyte determination in the adult brain actually requires a transient TH -free environment. Since endogenous repair of neurodegenerative (e.g. Parkinson, Alzheimer) or neuroinflammatory disease (Multiple Sclerosis) would require preferentially neurogenesis or oligodendrogenesis from NSC, respectively, the aim of our project is to decipher the molecular mechanisms by which TH orient the glial versus neuronal fate. As neuronal versus glial decisions during embryonic, post-embryonic and maturity are strongly spatially and temporally defined, we will address the question of how TH modulates these decisions using two distinct stages, adult neurogenesis and the perinatal period in mammals, with its parallel of pre-metamorphosis in amphibians. To this end, we will take advantage of state of the evolutionary conservation of TH signalling to address how TH modulates neuronal versus glial decisions in two classes of vertebrates: in the murine Subventricular Zone and in the optic nerve of pre-metamorphic Xenopus tadpoles. The results of our study will bring in depth knowledge of the links between TH availability, adult NSC functions and the programs regulating NSC fate decisions within the complex architecture of neurogenic regions. They could have significant consequences in understanding repair processes when proposing treatments for neurological diseases, notably Multiple Sclerosis. We will take advantage of state of the art techniques mastered in the participating laboratories to determine: 1) The cellular effects of TH availability on stem and progenitor cell biology (P1 P2) 2) The effects of T3 on specific cell populations (P1 P2) 3) Interactions between EGFR signalling and TH pathways on progenitor cell commitment (P1). 4) The consequences of demyelination on progenitor responses /commitment (P1 P2) To understand genetic regulations induced by TH in these cell fate decisions we will use transcriptomic approaches to determine genetic networks and nodes underlying TH action in defined cell populations e.g. FACS-isolated adult oligodendrocyte precursor cells (OPCs) or newly generated OPCs isolated from mice in hypothyroid states at the time of demyelination. TH-target genes so identified, that represent key nodes implicated in determining cell fate responses, will provide candidates for potential therapeutic targets. Results could have significant consequences in understanding repair processes when proposing treatments for pathologies (Multiple Sclerosis), where new oligodendrocytes capable of remyelination are needed. In contrast, in the case of stroke or certain neurodegenerative diseases, it may be of interest to generate in one step both neurons and glia, or just neurons.