Thyroid Hormone modulation of Oligodendrocyte and Neuronal progenitor commitment – OLGA

The originality of our approach relies on: (i) the use of in vivo experimental models, (ii) taking advantage of two species of vertebrates (mouse and xenopus), (iii) exploited under physiological and pathological conditions (models of demyelination). The methodologies are: (i) the use and production of transgenic animals, (ii) the successful in vivo vectorisation in the adult neural stem cells of thyroid hormone modulators, (iii) the use of sophisticated imaging techniques, (iv) the evaluation of repair efficiency based on electrophysiological measurements of nerve conduction.

To date, we have already demonstrated the existence of two sources of remyelinating cells whose responsiveness to a demyelination insult is different. In comparison to the remyelination produced by pre-existing adult oligodendrocytes precursors located in the white matter, our data illustrates the superiority of oligodendrocytes newly generated from the adult neural stem cells, to completely restore the loss of myelin observed in our animal models. We have identified the endocrine signal that specifically regulates the production of these mature myelinating oligodendrocytes.

These results should lead to the identification of new therapeutic targets to repair demyelinating lesions in neurological disorders, the most common of which is Multiple Sclerosis that affects more women than men, with a ratio of women to men of about three to one.

This project generated 4 high-impact research papers and several international conferences. Three additional articles are currently being finalized. Moreover, two books have been published for both the French and Anglo-Saxon audiences.

The project OLGA ANR-14-CE13-0022 is a basic research project coordinated by Barbara Demeneix (CNRS MNHN 7221). Bernard Zalc (ICM) is also associated. The project started in October 2014 and lasted 48 months. He received ANR contribution of 390,172 euros.

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.