Thyroid-specific enhancer-binding protein (T/EBP), also called thyroid transcription factor 1 (TTF1) or NKX2.1, is a homeodomain-containing transcription factor that plays a role in organogenesis of the thyroid, lung, and ventral forebrain. It also regulates expression of thyroid and lung-specific genes, including 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. A mouse lacking T/EBP expression is missing the thyroid and pituitary, and has severe defects in the lung and hypothalamus. Thus, it appears that T/EBP is a master regulatory gene involved in the genesis of these organs by either directly or indirectly activating or suppressing downstream target genes. The T/ebp-null mouse provides an excellent animal model to study the role of T/EBP in the mechanism of organogenesis during development. Using T/ebp-null mouse embryo lungs as compared with wild-type littermate lungs, recent efforts focused on identifying genes that are regulated by T/EBP during development and that are involved in organogenesis. Two novel lung-enriched genes that appear to be a direct target gene of T/EBP were isolated by PCR-based subtraction library screening. One of the genes encodes Uteroglobin-related protein 1 (UGRP1) that is a secretory protein and is mainly expressed in the epithelial cells of the trachea, bronchus, and bronchioles. The expression was reduced in antigen-treated inflamed mouse lungs, suggesting its possible role in lung inflammation. Efforts are underway to determine whether UGRP1 is involved in inflammation. The other novel gene belongs to a tight junction family of proteins. The gene, claudin-18 produces two isoforms through alternative splicing; one is lung-specific and the other is stomach-specific. They are indeed present at tight junctions in the epithelial cells as demonstrated by electron microscopy. Among other claudin family members expressed in the lung, claudin-18 lung-specific isoform is the only claudin whose expression is strictly dependent on T/EBP. This may suggest a specialized role for claudin-18 in the lung that is under the regulation of T/EBP. Whether claudin-18 plays a role in lung branching morphogenesis is unclear at this moment. In order to understand the role of T/EBP during development and in homeostasis of the thyroid and lung, a conditional knockout mouse line that deletes T/EBP expression only in the thyroid or lung at any given time has been being developed. Study is currently under way to characterize this mouse line.
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