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apoptosis (2), while many of the remaining cells migrate to form new interneurons in the U Page 1 of 17 (page number not for citation purposes) olfactory lobe (3).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...
There is a pressing need for high throughput methods to assess potential effects of endocrine disrupting chemicals (EDCs). released into the environment. Currently our ability to identify effects in vitro exceeds that for in vivo monitoring. However, only in vivo analysis provides the full spectrum of physiological impacts exerted by a given chemical. With the aim of finding a physiological system compatible with automatic plate reading we tested the capacity of early embryonic stage Xenopus laevis tadpoles to monitor thyroid hormone (TH) disruption. Fluorescent transgenic X. laevis embryos bearing a TH/bZIP-eGFP construct, placed in 96 well plates, were used for a physiological-based screen for potential TH signaling disruptors. Using stage NF-45 embryos (time of thyroid gland formation) allowed rapid detection of chemical interference with both peripheral TR signaling and production of endogenous TH. Nanomolar concentrations of TH receptor agonists could be detected within 72 h. Moreover, when testing against a 5nM T3 challenge, the effects of inhibitors of TH production were revealed, including inhibitors of TH synthesis, (methimazole: 1 mM or sodium perchlorate: 3.56 microM), as well as antagonists acting at the receptor level (NH3: 2 microM) and a deiodinase inhibitor (iopanoic acid: 10 microM). Finally, we show that the thyroid disrupting activities of BPA (10 microM) and TBBPA (1 microM) can also be detected in this rapid screening protocol. Finally, this noninvasive technology using an automatic reading system shows low variability (around 5%) and permits detection of subtle changes in signaling by EDCs that either inhibit or activate TH signaling in vivo.
After differential screening of a cDNA library constructed from quail neuroretina cells infected with the v-myc containing avian retrovirus MC29, we have isolated a cDNA clone Pax-QNR, homologous to the murine Pax6 which is mutated in the autosomal dominant mutation small eye (Sey) of the mouse and aniridia in man. Here we report the characterization of Pax-QNR/Pax-6 expression in the chicken, quail, and mouse pancreas. In situ hybridization performed with E3 chick embryos demonstrated that, in addition to the documented expression of Pax-QNR/Pax-6 in the neural tube, this gene is also expressed in the pancreatic bud. This expression is later restricted to discrete parts of the organ. From bacterially expressed Pax-QNR peptides we obtained rabbit antisera (paired domain, serum 11; domain between paired and homeo, serum 12; homeodomain, serum 13; and carboxyl-terminal part, serum 14) capable of specifically recognizing Pax-QNR/Pax-6 proteins (48, 46 kilodaltons) in cell lines derived from alpha- and beta-pancreatic cells, but not from exocrine derived cell lines. We conclude that Pax-QNR/Pax-6 represents another gene expressed both in the endocrine pancreas and neuro-ectodermic tissues.
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