title: Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism.
abstract: Kinesins, including the kinesin 2/KIF3 molecular motor, play an important role in intracellular traffic and can deliver vesicles to distal axon terminals, to cilia, to nonpolarized cell surfaces or to epithelial cell basolateral membranes, thus taking part in the establishment of cellular polarity. We report here the consequences of kinesin 2 motor inactivation in the thyroid of 3-week-old Kif3a(Δ)(/flox) Pax8(Cre/)(+) mutant mice. Our results indicate first that 3-week-old Pax8(Cre/)(+) mice used in these experiments present minor thyroid functional defects resulting in a slight increase in circulating bioactive TSH and intracellular cAMP levels, sufficient to maintain blood thyroxine levels in the normal range. Second, Kif3a inactivation in thyrocytes markedly amplified the phenotype observed in Pax8(Cre/)(+) mice, resulting in altered TSH signaling upstream of the second messenger cAMP and mild hypothyroidism. Finally, our results in mouse embryonic fibroblasts indicate that Kif3a inactivation in the absence of any Pax8 gene alteration leads to altered G protein-coupled receptor plasma membrane expression, as shown for the β2 adrenergic receptor, and we suggest that a similar mechanism may explain the altered TSH signaling and mild hypothyroidism detected in Kif3a(Δ)(/flox) Pax8(Cre/)(+) mutant mice.
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire IRIBHM, Institut de Biologie et de Médecine Moléculaires IBMM, Université Libre de Bruxelles ULB, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: D'Amico
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gayral
authors.forename: Claude
authors.initials: C
authors.lastname: Massart
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Van Sande
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Reiter
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Dumont
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schurmans
mesh_terms: D000818:Animals; D007037:Hypothyroidism / Q000209:etiology* / Q000378:metabolism*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin
chemical_list: C490202:Kif3a protein, mouse; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D013972:Thyrotropin; D016547:Kinesins