Japanese

Lessons from the TRH gene and TRH knockout mice Masanobu Yamada 1 1Department of Molecular and Clinical Medicine, Gunma University Graduate School of Medical Science Keyword: TRH , 遺伝子 , プロモーター , ノックアウトマウス pp.398-406
Published Date 2003/6/10
DOI https://doi.org/10.11477/mf.1431100322
  • Abstract
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 Thyrotropin-releasing hormone(pGlu-His-ProNH2, TRH)is a hypothalamic hormone that stimulates thyrotropin(TSH)synthesis and secretion in the anterior pituitary and plays a critical role in the hypothalamus-pituitary-thyroid axis. TRH is also found in many organs including the extrahypothalamic central nervous, cardiovascular, reproductive systems, and gastrointestinal tract. However, the precise mechanism by which thyroid hormone regulates the TRH gene in hypothalamus and the role of TRH in peripheral organs remains unclear.

 To investigate the molecular mechanism of thyroid hormone regulation of the TRH gene, we first cloned and characterized the human and mouse preproTRH genes. The gene is approximately 3.0 kb in length containing three exons and two introns. The human preproTRH has a characteristic structure containing 6 repetitive progenitor sequences, while the mouse has 5 copies. The transient transfection analysis revealed that the preproTRH gene is transcriptionally regulated by thyroid hormone, T3, and the thyroid hormone response element is located close to the transcription start site. A corepressor, NcoR, stimulates the basal promoter activity of the TRH gene.

 To investigate the roles of TRH in the development and physiology of the pituitary thyrotrophs and in the peripheral organs, we next used homologous recombination to generate mice that lack TRH(TRH-/-). These TRH-/-mice were fertile, viable, and developed normally. There was no apparent abnormality in central nervous system, gastrointestinal tract, reproductive system as well as visual system. However,immunohistochemical analysis revealed a number of TSH-immunopositive cells in the TRH-/-pituitary on embryonic day 17.5 and at birth(postnatal day 0.5, P0.5), which were similar to those in the wild-type, indicating no requirement of embryonic TRH for the development of pituitary thyrotrophs. In contrast, apparent decreases in number and level of staining of TSH-immunopositive cells were observed after P10mutant pituitary. Similar decrease was observed in 8 weeks mutant pituitary. Consistent with these morphological results, TRH-/-mice showed normal thyroid hormone levels at birth, but the subsequent postnatal increase was depressed resulting in hypothyroidism. To evaluate the mechanism underlying this hypothyroidism, we measured TSH-βandαmRNA levels in the TRH-/-and wild-type pituitary. Despite hypothyroidism in the mutant mice, both the pituitary TSHβandαmRNA levels were paradoxically lower than those of the wild-type pituitary. These phenotypic changes were specific on the pituitary thyrotrophs but not on the other pituitary hormone producing cells.

 These findings indicated that 1)TRH is essential only for the postnatal maintenance of the normal function of pituitary thyrotrophs, including the normal feedback regulation of the TSH gene by thyroid hormone, 2)embryonic TRH is not required for normal development of the fetal pituitary thyrotroph, and 3)as reflecting its name, TRH has more critical action especially on the pituitary thyrotrophs than on other pituitary hormone producing cells.


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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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