Homeodomain transcription factor T/EBP (thyroid-specific enhancer-binding protein), also called thyroid transcription factor 1 (TTF1) or NKX2.1, regulates expression of thyroid and lung-specific genes such as those encoding thyroid peroxidase, thyroglobulin, and TSH receptor in the thyroid, and surfactant proteins A, B, and C, and Clara cell secretory protein in the lung, respectively. T/EBP is also essential for genesis of the thyroid, lung, and ventral forebrain, evidenced by the phenotypes of T/ebp-null mice that die at birth, missing the thyroid and pituitary, and having severe defects in the lung and hypothalamus. Thus, T/EBP appears to be one of the master regulatory genes involved in the genesis of these organs by either directly or indirectly activating or suppressing downstream target genes.? ? In order to understand the role of T/EBP during development and in the homeostasis of the thyroid, a conditional knockout mouse line that deletes T/EBP expression only in the thyroid was developed. Thyroids from embryos and adults at various ages with and without T/EBP deletion were subjected to detailed examination by histopathological and immunohistochemical analyses, and for the degree of T/EBP gene deletion by southern blotting and T/EBP mRNA levels by Northern blotting, and biochemical analysis of TSH levels in serum. A three dimensional thyroid primary culture system was also developed to study the role of T/EBP in thyroid differentiation in vitro. These results demonstrated that T/EBP is required for maintenance of the normal architecture and function of differentiated thyroids. ? ? Thyroid phenotypes of the T/ebp-thyroid conditional knockout mice suggested the possible presence of a stem-cell like population of cells in the thyroid. FACS analysis of thyroid cells demonstrated that T/EBP may be involved in maintaining such a population of cells having stem-cell like activities. Based on the hypothesis that mice with deleted T/EBP may be susceptible to chemical carcinogens, chemical carcinogenesis studies are in progress. Efforts are also focused to establish tumor cell lines derived from thyroids of T/ebp-thyroid conditional knockout mice with and without T/EBP deletion, in order to understand whether T/EBP plays a role in carcinogenesis process.?
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