In human thyroid,
caveolin-1 is localized at the apex of thyrocytes, but its role there remains unknown. Using immunohistochemistry, (127)I imaging, transmission electron microscopy, immunogold electron microscopy, and quantification of H(2)O(2), we found that in
caveolin-1 knockout mice thyroid cell homeostasis was disrupted, with evidence of oxidative stress, cell damage, and apoptosis. An even more striking phenotype was the absence of
thyroglobulin and
iodine in one-half of the follicular lumina and their presence in the cytosol, suggesting that the
iodide organification and binding to
thyroglobulin were intracellular rather than at the apical membrane/extracellular
colloid interface. The latter abnormality may be secondary to the observed mislocalization of the
thyroid hormone synthesis machinery (
dual oxidases, thyroperoxidase) in the cytosol. Nevertheless, the overall uptake of radioiodide, its organification, and secretion as
thyroid hormones were comparable to those of wild-type mice, suggesting adequate compensation by the normal TSH retrocontrol. Accordingly, the levels of free
thyroxine and TSH were normal. Only the levels of free
triiodothyronine showed a slight decrease in
caveolin-1 knockout mice. However, when TSH levels were increased through low-
iodine chow and
sodium perchlorate, the induced
goiter was more prominent in
caveolin-1 knockout mice. We conclude that
caveolin-1 plays a role in proper
thyroid hormone synthesis as well as in cell number homeostasis. Our study demonstrates for the first time a physiological function of
caveolin-1 in the thyroid gland. Because the expression and subcellular localization of
caveolin-1 were similar between normal human and murine thyroids, our findings in
caveolin-1 knockout mice may have direct relevance to the human counterpart.