Endocrine Abstracts

Thyroid hormones (THs) are pivotal in orchestrating neurodevelopment and regulating adult brain function. Recent investigations into rodents have unveiled the potent effects THs have in adult neurogenic niches, particularly in the subventricular zone (SVZ), the brain’s largest neural stem cell (NSC) niche. THs influence neurogliogenesis, finely controlling processes such as cell cycle and progenitor determination, directing either neuronal or oligodendroglial commitment. Among the intricate network of regulators modulating TH availability and action in the SVZ, the role of type two deiodinase (DIO2), the primary T4-activating enzyme, remains unexplored. DIO2, is mainly expressed in astrocytes and tanycytes, regulating local T3 production in the brain and hypothalamic-pituitary axis. Although no inactivating mutations in the DIO2 gene have been documented in humans, DIO2 gene polymorphisms correlate with conditions such as mental retardation, bipolar disorder, and insulin resistance. Here, our study aimed to investigate DIO2 function in regulating NSC behavior in the adult SVZ, notably proliferation, determination. In particular, we will analyze in more detail a potential function of DIO2 in the release of NSC from quiescence, a process for which underlying molecular mechanisms are still far from being elucidated. Using single-cell RNA sequencing analysis in young adult mice SVZ, a strong association between DIO2 expression and NSC quiescent state was revealed. Subsequent RNAscope analysis was performed to assess DIO2 expression pattern in the different SVZ cell types not only in the SVZ but also along the RMS-OB axis. Moreover, we tested the effects of administering exogenous deiodinase inhibitors ex vivo, using neurosphere assay. to better analyze the action of DIO2 on NSC proliferation and neuron/glia determination. Altogether, these data revealed an intriguing role of DIO2 in the tight control of NSC proliferation, notably on NSC activation Moreover, functional implications of DIO2 were assessed through behavioral tests on DIO2-lacking mice (Dio2 KO), using olfactory memory and odor discrimination tests as non-invasive biomarkers of SVZ status. Dio2 KO mice displayed impaired odor memory, suggesting a functional role of DIO2 in adult SVZ-neurogenesis In sum, we highlight the contribution of DIO2 as a key regulator of adult SVZ neurogliogenesis. Our findings also point towards the need for further experiments, specifically focusing on regulating DIO2 expression in vivo, that will help shedding light on its implications in brain function and pathology.