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apoptosis (2), while many of the remaining cells migrate to form new interneurons in the U Page 1 of 17 (page number not for citation purposes) olfactory lobe (3).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...

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