title: The loss of the chloride channel, ClC-5, delays apical iodide efflux and induces a euthyroid goiter in the mouse thyroid gland.
abstract: Genetic inactivation of ClC-5, a voltage-gated chloride channel prominently expressed in the kidney, leads to proteinuria because of defective apical endocytosis in proximal tubular cells. Because thyroid hormone secretion depends on apical endocytosis of thyroglobulin (Tg), we investigated whether ClC-5 is expressed in the thyroid and affects its function, using Clcn5-deficient knockout (KO) mice. We found that ClC-5 is highly expressed in wild-type mouse thyroid ( approximately 40% of mRNA kidney level). The protein was immunolocalized at the apical pole of thyrocytes. In Percoll gradients, ClC-5 overlapped with plasma membrane and early endosome markers, but best codistributed with the late endosomal marker, Rab7. ClC-5 KO mice were euthyroid (normal T4 and TSH serum levels) but developed a goiter with parallel iodine and Tg accumulation (i.e. normal Tg iodination level). When comparing ClC-5 KO with wild-type mice, thyroid 125I uptake after 1 h was doubled, incorporation into Tg was decreased by approximately 2-fold, so that trichloroacetic acid-soluble 125I increased approximately 4-fold. Enhanced 125I- efflux upon perchlorate and presence of 125I-Tg as autoradiographic rings at follicle periphery demonstrated delayed iodide organification. Endocytic trafficking of 125I-Tg toward lysosomes was not inhibited. Expression of pendrin, an I-/Cl- exchanger involved in apical iodide efflux, was selectively decreased by 60% in KO mice at mRNA and protein levels. Thus, ClC-5 is well expressed in the thyroid but is not critical for apical endocytosis, contrary to the kidney. Instead, the goiter associated with ClC-5 KO results from impaired rate of apical iodide efflux by down-regulation of pendrin expression.
authors.affiliation: Cell Biology Unit-ICP/UCL 7541, 75 av Hippocrate, B-1200 Brussels, Belgium. vandenhove@cell.ucl.ac.be
authors.forename: Marie-France
authors.initials: MF
authors.lastname: van den Hove
authors.forename: Karine
authors.initials: K
authors.lastname: Croizet-Berger
authors.forename: François
authors.initials: F
authors.lastname: Jouret
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Guggino
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Courtoy
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000096:biosynthesis / Q000378:metabolism; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006042:Goiter / Q000235:genetics / Q000473:pathology*; D007454:Iodides / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D015233:Models, Statistical; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D000076988:Sulfate Transporters; D013954:Thyroglobulin / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D013963:Thyroid Hormones / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D027321:Anion Transport Proteins; C471345:CLC5 protein, mouse; D018118:Chloride Channels; D017931:DNA Primers; D007454:Iodides; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D013963:Thyroid Hormones; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D012313:RNA; D013954:Thyroglobulin; D020691:rab GTP-Binding Proteins