Adult neural stem cell cycling in vivo requires thyroid hormone and its alpha receptor

Abstract

Thyroid hormones (TH) are essential for brain development. However, information on if and how this key endocrine factor affects adult neurogenesis is fragmentary. We thus investigated the effects of TH on proliferation and apoptosis of stem cells in the subventricular zone (SVZ), as well as on migration of transgene-tagged neuroblasts out of the stem cell niche. Hypothyroidism significantly reduced all three of these processes, inhibiting generation of new cells. To determine the mechanisms relaying TH action in the SVZ, we analyzed which receptor was implicated and whether the effects were played out directly at the level of the stem cell population. The α TH receptor (TRα), but not TRβ, was found to be expressed in nestin positive progenitor cells of the SVZ. Further, use of TRα mutant mice showed TRα to be required to maintain full proliferative activity. Finally, a direct TH transcriptional effect, not mediated through other cell populations, was revealed by targeted gene transfer to stem cells in vivo. Indeed, TH directly modulated transcription from the c-myc promoter reporter construct containing a functional TH response element containing TRE but not from a mutated TRE sequence. We conclude that liganded-TRα is critical for neurogenesis in the adult mammalian brain.Key words: subventricular zone • NSC • TH nderstanding the genetic regulation of neural stem cell (NSC) maintenance, division, and differentiation is a central problem in NSC biology. The identification of subventricular astrocytes as NSCs in the subventricular zone (SVZ) of the adult rodent brain contributed to the confirmation of the existence of a neurogenic niche in this region (1). Although relatively quiescent and slow dividing, the NSC population residing in this site gives rise to rapidly dividing neural progenitors, which in turn generate neural precursors that have the ability to generate both neurons and glia. However, most cells emerging from the SVZ undergo apoptosis (2), while many of the remaining cells migrate to form new interneurons in the U Page 1 of 17 (page number not for citation purposes) olfactory lobe (3). Some cells may also generate glial cells in the corpus callosum (4). To exploit the therapeutic potential of endogenous stem cells, knowledge of the intrinsic and extrinsic mechanisms affecting NSC population size and expansion is needed. However, few studies have addressed endocrine control of NSC function, particularly in vivo (5).The thyroid hormones (TH) are essential for brain development in all vertebrates (6). The main secreted form of TH is thyroxine (T 4 ), which is converted to the biologically more active form triiodothyronine (T 3 ), in peripheral tissues. In each species studied, TH levels are highest during the period of most rapid brain growth and development, which in humans occurs during the first 2 yr of postnatal life. Lack of TH in early development causes severe neurological damage and results in cretinism in man (7). At the cellular level, TH action on specific cells and at specific phas...

Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior

“…Other in vivo studies show that TH could reverse impaired hippocampal neurogenesis during development 53 and in the adult SVZ. 26 Lemkine et al 26 found that TH influence precursor cell proliferation in the SVZ, using Ki67 and phosphorylated histone H3 as proliferation markers. The effect was not observed when BrdU incorporation was used, which led the authors to propose that hypothyroidism increased the number of progenitors in the resting state in the SVZ.…”

“…[20][21][22] TH action is mediated through T3 nuclear receptors, and T3 receptor deficiency or mutations also alter adult hippocampal structure and hippocampus-dependent behavior. 23,24 Very recently, TH have been implicated in adult neurogenesis, [25][26][27][28] but little is known on the functional consequences of TH actions on proliferation of neuronal progenitors.…”

Thyroid hormones and the control of cell proliferation or cell differentiation: Paradox or duality?

“…These data strongly suggest a potential therapeutic use of THs in Alzheimer's disease. Adult neural stem cells of the subventricular zone (SVZ) in mouse also require THs and TRα1 function (Lemkine et al, 2005). In these cells in vivo, THs-TRα1 likely act to inhibit the expression of c-Myc and cyclin D1, inducing their exit from the cell cycle.…”

Influence of thyroid hormones on nervous system development – brief review

“…The regulation of neurotransmitter release in the hippocampus was also influenced by the presence of thyroid hormones; electrophysiological studies of short-term synaptic plasticity showed that facilitation of paired pulse patterns were found to be extremely modified in animals with hypothyroidism, this condition being reversible with the administration of thyroid hormones [34]. Investigations on cell proliferation in the sub-ventricular zone (SVZ) of the hippocampus also demonstrated that T3 and its receptor alpha (TRα) play an important role in neurogenesis in this region [35]. Effects on extracellular matrix synthesis were also observed in cerebellum, since the absence of thyroid hormones delay laminin expression [36] [37], and their levels were 35% lower than control animals (Farwell et al, 1995 (Figure 2).…”