Transient hypothyroidism favors oligodendrocyte generation providing functional remyelination in the adult mouse brain

Abstract

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.

Thyroid hormone regulation of neural stem cell fate: From development to ageing

“…Similarly, low TH levels reduce the generation of immature hippocampal neurons in the adult SGZ . Taken together, these results show that TH acts as a neurogenic factor both in the SVZ and in the SGZ by promoting NSC commitment towards a neuronal fate …”

“…A few NSCs are also able to generate glial cells, both astrocytes and oligodendrocytes . However, the oligodendrogenic potential of SVZ‐NSCs strongly increases in response to a pharmacologically demyelinating insult . SVZ‐derived OPCs migrate towards the corpus callosum, the striatum and the cerebral cortex within close range of the lateral ventricle, where they differentiate into mature myelinating oligodendrocytes …”

“…In contrast, a TH‐free environment promotes the generation of new OPCs derived from SVZ‐NSCs under physiological and pathological conditions . Following a demyelinating insult, these newly generated SVZ‐OPCs generate mature myelinating oligodendrocytes in the corpus callosum .…”

“…In contrast, a TH‐free environment promotes the generation of new OPCs derived from SVZ‐NSCs under physiological and pathological conditions . Following a demyelinating insult, these newly generated SVZ‐OPCs generate mature myelinating oligodendrocytes in the corpus callosum . Compared to remyelination accomplished by resident parenchymal OPCs, myelin formed by oligodendrocytes derived from the SVZ has a normal thickness, and these newly generated OPCs provide functional remyelination, restoring normal conduction speed .…”

“…For instance, epidemiological data have shown that maternal hypothyroidism during the first trimester of pregnancy alters white/grey matter ratios, and is associated with a lower offspring general IQ and a decrease in verbal and motor performances during childhood . Moreover, recent experimental findings also showed that TH is a crucial regulator of NSC fate determination in the two main neurogenic niches in mammals . The question arises whether TH action converges on common pathways in embryonic neural progenitors.…”