Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism.
Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism.
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DOI：
10.1530/jme-12-0219
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发表时间：
2013-06
影响因子：
3.5
通讯作者：
Schurmans S
中科院分区：
文献类型：
--
作者：
D'Amico E;Gayral S;Massart C;Van Sande J;Reiter JF;Dumont JE;Robaye B;Schurmans S
驱动蛋白（包括驱动蛋白2/KIF 3分子马达）在细胞内运输中起重要作用，可将囊泡运送到轴突末梢、纤毛、非极化细胞表面或上皮细胞基底外侧膜，从而参与细胞极性的建立。我们在此报告了3周龄Kif 3a Δ/flox Pax 8 Cre/+突变小鼠甲状腺中驱动蛋白2运动失活的后果。我们的结果首先表明，在这些实验中使用的3周龄Pax 8 Cre/+小鼠存在轻微的甲状腺功能缺陷，导致循环生物活性TSH和细胞内cAMP水平略微增加，足以将血液T4水平维持在正常范围内。其次，甲状腺细胞中的Kif 3a失活显著放大了在Pax 8 Cre/+小鼠中观察到的表型，导致第二信使cAMP上游的TSH信号改变和轻度甲状腺功能减退。最后，我们在小鼠胚胎成纤维细胞中的结果表明，在没有任何Pax 8基因改变的情况下，Kif 3a失活导致GPCR质膜表达改变，如β2肾上腺素能受体所示，我们认为类似的机制可以解释在Kif 3a Δ/flox Pax 8 Cre/+突变小鼠中检测到的TSH信号转导改变和轻度甲状腺功能减退。
Kinesins, including the kinesin 2/KIF3 molecular motor, play an important role in intracellular traffic and can deliver vesicles to distal axon terminal, to cilia, to non-polarized cell surface or to epithelial cell basolateral membrane, thus taking part to the establishment of cellular polarity. We report here the consequences of the kinesin 2 motor inactivation in the thyroid of 3 week-old Kif3aΔ/flox Pax8Cre/+ mutant mice. Our results indicate first that 3 week-old Pax8Cre/+ 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 T4 levels in the normal range. Second, Kif3a inactivation in thyrocytes markedly amplified the phenotype observed in Pax8Cre/+ mice, resulting in an 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 GPCR 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 Kif3aΔ/flox Pax8Cre/+ mutant mice.