Adult neural stem cell fate is determined by thyroid hormone activation of mitochondrial metabolism

Abstract

ObjectiveIn the adult brain, neural stem cells (NSCs) located in the subventricular zone (SVZ) produce both neuronal and glial cells. Thyroid hormones (THs) regulate adult NSC differentiation towards a neuronal phenotype, but also have major roles in mitochondrial metabolism. As NSC metabolism relies mainly on glycolysis, whereas mature cells preferentially use oxidative phosphorylation, we studied how THs and mitochondrial metabolism interact on NSC fate determination.MethodsWe used a mitochondrial membrane potential marker in vivo to analyze mitochondrial activity in the different cell types in the SVZ of euthyroid and hypothyroid mice. Using primary adult NSC cultures, we analyzed ROS production, SIRT1 expression, and phosphorylation of DRP1 (a mitochondrial fission mediator) as a function of TH availability.ResultsWe observed significantly higher mitochondrial activity in cells adopting a neuronal phenotype in vivo in euthyroid mice. However, prolonged hypothyroidism reduced not only neuroblast numbers but also their mitochondrial activity. In vitro studies showed that TH availability favored a neuronal phenotype and that blocking mitochondrial respiration abrogated TH-induced neuronal fate determination. DRP1 phosphorylation was preferentially activated in cells within the neuronal lineage and was stimulated by TH availability.ConclusionsThese results indicate that THs favor NSC fate choice towards a neuronal phenotype in the adult mouse SVZ through effects on mitochondrial metabolism.

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 …”

“…In the adult SVZ, a hypothyroid state is also associated with lower numbers of both early committed neuronal progenitors and mature neuroblasts, thus decreasing migrating neuroblasts along the rostral migratory stream (RMS) . Similarly, low TH levels reduce the generation of immature hippocampal neurons in the adult SGZ .…”

“…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.…”

“…Moreover, NSC fate choice is associated with specific changes in metabolic status and mitochondrial morphology . Increasing evidence shows that a complex interplay between TH signalling and cell metabolism is involved in cell commitment and differentiation …”

Maternal photoperiodic programming enlightens the internal regulation of thyroid‐hormone deiodinases in tanycytes

“…T3 plays a direct role in both the control of neural cell proliferation and neuroglial differentiation in brain proliferative areas. 108,109 Tanycytes express proliferation and differentiation markers under seasonal (eg, vimentin, nestin) 105,110 and T3-mediated control (eg, shh) 107 and have been proposed as the substrate for neurogenic activity in the hypothalamus, stimulated by metabolic cues and growth factors. [111][112][113][114][115][116] Moreover, seasonal differences exist in hypothalamic cell proliferation [117][118][119] and neuronal differentiation.…”