The thyrotropin (TSH) receptor (TSHR) is a member of the heterotrimeric G protein-coupled family of receptors whose main function is to regulate thyroid cell proliferation as well as thyroid hormone synthesis and release. In this study, we generated a TSHR knockout (TSHR-KO) mouse by homologous recombination for use as a model to study TSHR function. TSHR-KO mice presented with developmental and growth delays and were profoundly hypothyroid, with no detectable thyroid hormone and elevated TSH. Heterozygotes were apparently unaffected. Knockout mice died within 1 week of weaning unless fed a diet supplemented with thyroid powder. Mature mice were fertile on the thyroid-supplemented diet. Thyroid glands of TSHR-KO mice produced uniodinated thyroglobulin, but the ability to concentrate and organify iodide could be restored to TSHR-KO thyroids when cultured in the presence of the adenylate cyclase agonist forskolin. Consistent with this observation was the lack of detectable sodium-iodide symporter expression in TSHR-KO thyroid glands. Hence, by using the TSHR-KO mouse, we provided in vivo evidence, demonstrating that TSHR expression was required for expression of sodium-iodide symporter but was not required for thyroglobulin expression, suggesting that the thyroid hormone synthetic pathway of the mouse could be dissociated into TSHR-dependent and -independent steps.

Intrathyroidal T-cell accumulation in autoimmune thyroid disease is highly restricted and points to the primacy of T cells in causing thyroid disorders. These results present the possibility of using antibodies to the T-cell receptor for the specific inhibition of abnormal T-cell function in autoimmune thyroid disease.

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Human skin was labeled with purified antibodies against type I and m collagens and against their extension aminopropeptides by using the ferritin technique. Both aminopropeptides were visualized mainly along thin collagenous fibrils (diameter, 20-40 nm) and rarely in nonfibrillar regions of the skin. The labeling showed a periodicity of 60-65 nm resembling the D (67 nm) stagger of collagen molecules. Blocking of antibodies with aminopropeptides and treatment of tissues with procollagen NH2-terminal protease abolished labeling. Antibodies against type I collagen uniformly labeled -80% of the fibrils (diameter, 20-80 nm), while reaction with antibodies against type m collagen was restricted to thin fibrils. It is currently thought that the aminopropeptides of procollagen molecules are cleaved after they are released from the cell and before fibril formation. Our data indicate that aminopropeptides are removed at the fibrillar level and that fibril growth can be regulated by extracellular procollagen processing. Type I and III collagens are major components of the dermis and are organized into fibrils varying considerably in diameter. Distinct growth of fibrils is observed during development and may be disturbed in certain skin diseases (1). The mechanism of controlling this process is unknown. It has also not been established whether type I and III collagens are present in the same fibrils. Both collagens can form D-staggered fibrils in vitro showing identical cross-striations when examined in the electron microscope (2). Because specific antibodies against various collagens and procollagens are available (3, 4), it is feasible to identify distinct types of collagenous proteins at the ultrastructural level in situ, as was recently done for type III collagen (5).Interstitial collagens are synthesized in the form of procollagens that possess additional extension amino-and carboxypropeptides. Each precursor-specific peptide is removed by specific proteases (procollagen NH2-terminal and COOH-terminal proteases) presumably after release of procollagens from the cell (6). Cell and organ culture studies indicated different kinetics in the processing of type I and III procollagens (7-9). After cleavage, the aminopropeptides persist for some time in the extracellular space, as shown by immunofluorescence staining with antibodies against these peptides (3, 4).A functional role for extension aminopropeptides in the control of fibril growth was first suggested in studies of dermatosparactic animals, which, due to a defective NH2-terminal protease, accumulate an intermediate form of type I procollagen (pN-collagen) in the skin and other organs (10, 11). The collagenous fibrils appeared thin and hieroglyphic (12, 13) and could be stained with antibodies against the aminopropeptide by using a ferritin label (13). Small amounts of type I and III pN-collagens could also be extracted from the skin of growing animals (14-18). It was suggested (3, 14, 19) that these aminopropeptides are structural elements ofimmature or th...