DEIODINASE 2 AND ADULT NEUROGLIOGENESIS IN THE SUBVENTRICULAR ZONE: A TALE OF TWO WAVES

Thyroid hormones (THs) are essential for neurodevelopment and brain function. Studies in rodents revealed that they strongly influence adult neurogenic regions, particularly the subventricular zone (SVZ). A key regulator for local THs availability is type 2 deiodinase (DIO2), responsible for T4 conversion into the transcriptionally active T3. However, its role in the SVZ remains unclear. Here, we investigated the role of DIO2 in regulating neural stem cell (NSC) behavior in the adult mouse SVZ.
Using single-cell RNA-sequencing, we unexpectedly found that Dio2 expression was almost exclusive to quiescent NSCs (qNSCs). To determine the functional relevance of this finding, we analyzed adult neurogliogenesis in DIO2-deficient mice (Dio2 KO). An increase in the density of SVZ progenitors was observed, coupled with increased cell proliferation, a classical hallmark of hypothyroidism. Intracerebroventricular administration of cytarabine further revealed that this overproliferative state stemmed at least partially from qNSCs overactivation. Moreover, neurosphere assays revealed that this effect was not solely due to parenchymal THs levels, but rather to cell-autonomous alterations derived from DIO2 absence.
Beyond this early first-wave, we identified a second wave of DIO2 influence, later during lineage commitment. We observed alterations in neurogliogenesis, as DIO2 absence led to the aberrant differentiation of SVZ-derived oligodendrocytes, while also hindering neuronal differentiation and integration in the olfactory bulbs. This latter effect is likely related to disrupted TH-levels, leading to olfactory impairments.
Here, we highlight DIO2 as a key contributor to adult SVZ neurogliogenesis, acting at multiple levels to control NSC quiescence, neurogliogenic lineage progression, and functional behavior.