Defective thyroglobulin storage in LDL receptor-associated protein-deficient mice.
The molecular chaperone receptor-associated protein (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 that it may affect Tg trafficking in various manners. To elucidate RAP function, we have studied the thyroid phenotype in RAP-knockout (RAP-KO) mice and found a reduction of Tg aggregates into thyroid follicles. Serum Tg levels were significantly increased compared with those of wild-type (WT) mice, suggesting a directional alteration of Tg secretion. In spite of these abnormalities, hormone secretion was maintained as indicated by 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 nevertheless sufficient to provide normal hormone secretion. Serum TSH 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 the establishment of Tg reservoirs, but its absence does not affect hormone secretion.
Lisi
Simonetta
S
Department of Endocrinology, University of Pisa, via Paradisa 2, I-56124 Pisa, Italy.
Botta
Roberta
R
Pinchera
Aldo
A
Collins
A Bernard
AB
Refetoff
Samuel
S
Arvan
Peter
P
Bu
Guojun
G
Grasso
Lucia
L
Marshansky
Vladimir
V
Bechoua
Shaliha
S
Hurtado-Lorenzo
Andres
A
Marcocci
Claudio
C
Brown
Dennis
D
McCluskey
Robert T
RT
Marinò
Michele
M
D000818:Animals; D001692:Biological Transport; D005260:Female; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000378:metabolism; D013954:Thyroglobulin / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism
D026563:LDL-Receptor Related Protein-Associated Protein; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D011973:Receptors, LDL; D013954:Thyroglobulin; D013974:Thyroxine