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.
Highlights
In Multiple Sclerosis (MS) neurological disability results from myelin and axonal degeneration
To address this question we investigated the role of hypothyroidism in generating oligodendrocyte progenitors in the adult Sub-Ventricular Zone (SVZ)
CPZ has the experimental advantage that the process of demyelination is temporally separated from the subsequent process of remyelination, allowing the latter to be studied without the complication of ongoing demyelination (Franklin, 2015)
Summary
In Multiple Sclerosis (MS) neurological disability results from myelin and axonal degeneration. Inflammation-induced loss of myelin renders axons more susceptible to injury, leading to greater probability of permanent handicap and accumulated disease burden (Dutta and Trapp, 2011; Mahad et al, 2015). Alongside available anti-inflammatory treatments, current therapeutic strategies aim at enhancing myelin repair. Screening of repurposing molecules favoring proliferation, differentiation and maturation of endogenous oligodendrocyte precursor cells (OPCs) have been deployed (Buckley et al, 2010; Deshmukh et al, 2013; Mei et al, 2014; Najm et al, 2015)
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