In the adult brain, both neurons and oligodendrocytes can be generated from neural stem cells located within the Sub-Ventricular Zone (SVZ). Physiological signals regulating neuronal versus glial fate are largely unknown. Here we report that a thyroid hormone (T₃)-free window, with or without a demyelinating insult, provides a favorable environment for SVZ-derived oligodendrocyte progenitor generation. After demyelination, oligodendrocytes derived from these newly-formed progenitors provide functional remyelination, restoring normal conduction. The cellular basis for neuronal versus glial determination in progenitors involves asymmetric partitioning of EGFR and TRα1, expression of which favor glio- and neuro-genesis, respectively. Moreover, EGFR⁺ oligodendrocyte progenitors, but not neuroblasts, express high levels of a T₃-inactivating deiodinase, Dio3. Thus, TRα absence with high levels of Dio3 provides double-pronged blockage of T₃ action during glial lineage commitment. These findings not only transform our understanding of how T₃ orchestrates adult brain lineage decisions, but also provide potential insight into demyelinating disorders.

In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely. A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules. In this transgenic, the green fluorescent protein reporter is fused to E. coli nitroreductase and expressed specifically in myelinating oligodendrocytes. Nitroreductase converts the innocuous pro-drug metronidazole to a cytotoxin. Spontaneous remyelination occurs after metronidazole-induced demyelinating responses. As tadpoles are transparent, these events can be monitored in vivo and quantified. At the end of metronidazole-induced demyelination, tadpoles were screened in water containing the compounds tested. After 72 h, remyelination was assayed by counting numbers of oligodendrocytes per optic nerve. Among a battery of molecules tested, siponimod, a dual agonist of sphingosine-1-phosphate receptor 1 and 5, was among the most efficient favoring remyelination. Crispr/cas9 gene editing showed that the promyelinating effect of siponimod involves the sphingosine-1-phosphate receptor 5. This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known promyelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.

Myelin, rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and myelination patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstructions, we report that in mouse cortex demyelination as subtle as the loss of a single oligodendrocyte can trigger robust cell replacement and remyelination timed by myelin breakdown. This results in reliable reestablishment of the original myelin pattern along continuously myelinated axons, while in parallel, patchy isolated internodes emerge on previously unmyelinated axons. Therefore, in mammalian cortex, internodes along partially myelinated cortical axons are typically not reestablished, suggesting that the cues that guide patchy myelination are not preserved through cycles of de- and remyelination. In contrast, myelin sheaths forming continuous patterns show remarkable homeostatic resilience and remyelinate with single axon precision.

In May 1868, Jean Martin Charcot (1825–93) (Fig. 1A) delivered a series of major lectures, establishing multiple sclerosis as a novel disease of the nervous system. Delving into the early 19th century medico-scientific literature illustrates how confusions delayed the identification of multiple sclerosis as a single nosological entity. The confusion arose in part from the difficulty to relate polymorph symptoms to the same disease as clinical signs are highly variable during the course of the disease, reflecting either spinal, or cerebrospinal or purely cerebral neurological symptoms. Charcot’s merit was to realize, applying his rigorous methodology inherited from Laennec (1781–1826) and Claude Bernard (1813–78), to bring together clinical observation, anatomo-pathology and physiology. This approach, along with detailed observations from others, led to Charcot’s proposition that these apparently unrelated symptoms belonged to the same disease, which he named Sclérose en plaques, a term that (from 1954) became multiple sclerosis in the English literature. Here I wish to commemorate the 150th anniversary of Charcot’s brilliant demonstration and tentatively decipher the reasoning that led Charcot to successfully ‘extract the sclérose en plaques from the chaos of chronic myelitis’.