Submitted on July 29, 2005
Accepted on November 16, 2005
DEFECTIVE THYROGLOBULIN (Tg) STORAGE IN LDL RECEPTOR ASSOCIATED PROTEIN (RAP) DEFICIENT MICE
Simonetta Lisi1, Roberta Botta1, Aldo Pinchera1, A. Bernard Collins2, Samuel Refetoff3, Peter Arvan4, Guojun Bu5, Lucia Grasso1, Vladimir Marshansky6, Shaliha Bechoua6, Andres Hurtado-Lorenzo5, Claudio Marcocci1, Dennis Brown6, Robert T McCluskey1, and Michele Marino1*
1 Endocrinology, University of Pisa, Pisa, Italy
2 Pathology, MGH Harvard Med. School, Boston, USA
3 Medicine and Peditrics, University of Chicago, Chicago, USA
4 Metabolism, University of Michigan, Ann Arbor, USA
5 Pediatrics, Washington University, St. Louis, USA
6 Prog. Membrane Biology, MGH Harvard Med. School, Charlestown, USA
* To whom correspondence should be addressed. E-mail: m.marino{at}endoc.med.unipi.it.
The molecular chaperone RAP is required for biosynthesis of megalin, an endocytic receptor for follicular thyroglobulin (Tg), the thyroid hormone precursor. RAP also binds to Tg itself, suggesting it may affect Tg trafficking in various manners. To elucidate RAP function, here we studied the thyroid phenotype in RAP KO mice and found a reduction of Tg aggregates into thyroid follicles. Serum Tg levels were significantly increased compared with WT mice, suggesting a directional alteration of Tg secretion. In spite of these abnormalities, hormone secretion was maintained, as indicated by the normal serum thyroxine levels. Because Tg in thyroid extracts from RAP KO mice contained thyroxine residues as in WT mice, we concluded that in RAP KO mice follicular Tg, although reduced, was however sufficient to provide a normal hormone secretion. Serum thyroid stimulating hormone was increased in RAP KO mice and although no thyroid enlargement was observed, some histological features resembling early goiter were present. Megalin was decreased in RAP KO mice, but this did not affect thyroid function probably because of the concomitant reduction of follicular Tg. In conclusion, RAP is required for establishment of Tg reservoirs, but its absence does not affect hormone secretion.
