MafB Interacts With Gcm2 and Regulates Parathyroid Hormone Expression and Parathyroid Development
MafB Interacts With Gcm2 and Regulates Parathyroid Hormone Expression and Parathyroid Development
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DOI：
10.1002/jbmr.458
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发表时间：
2011-10-01
影响因子：
6.2
通讯作者：
Kataoka, Kohsuke
中科院分区：
文献类型：
--
作者：
Kamitani-Kawamoto, Akiyo;Hamada, Michito;Kataoka, Kohsuke
血清钙和磷酸盐稳态受甲状旁腺分泌的甲状旁腺激素（PTH）的重要调节。甲状旁腺由双侧甲状旁腺-胸腺共同原基发育而来。在小鼠中，转录因子Glial cell missing 2（Gcm 2）的表达开始于胚胎第9.5天（E9.5）的原基的背侧/前部，指定甲状旁腺结构域。在E15.5时，甲状旁腺原基与胸腺原基分离，并迁移到甲状腺旁的成年位置。基因消融gcm 2导致小鼠甲状旁腺发育不全，表明Gcm 2对早期甲状旁腺器官形成至关重要。然而，甲状旁腺发育后期的调控机制尚不清楚。在这里，我们表明，转录激活因子v-maf肌肉腱膜纤维肉瘤癌基因同源物B（Maf B）是发育中表达的甲状旁腺细胞后E11.5。MafB表达在gcm 2基因敲除小鼠的甲状旁腺原基中丢失。mafB（+/-）小鼠的甲状旁腺错误定位在胸腺和甲状腺之间。在mafB（-/-）小鼠中，甲状旁腺未与胸腺分离。此外，在mafB（-/-）小鼠中，PTH表达和分泌受损; PTH靶基因之一的肾cyp 27 b1的表达水平降低;骨矿化减少。我们还表明，虽然Gcm 2单独不刺激PTH基因启动子，它与MafB协同激活PTH表达。总之，我们的研究结果表明，MafB调节甲状旁腺发育的后期步骤，即从胸腺分离并向甲状腺迁移。MafB还与Gcm 2协同调节PTH的表达。(C)2011年美国骨与矿物质研究学会。
Serum calcium and phosphate homeostasis is critically regulated by parathyroid hormone (PTH) secreted by the parathyroid glands. Parathyroid glands develop from the bilateral parathyroid-thymus common primordia. In mice, the expression of transcription factor Glial cell missing 2 (Gcm2) begins in the dorsal/anterior part of the primordium on embryonic day 9.5 (E9.5), specifying the parathyroid domain. The parathyroid primordrium then separates from the thymus primordium and migrates to its adult location beside the thyroid gland by E15.5. Genetic ablation of gcm2 results in parathyroid agenesis in mice, indicating that Gcm2 is essential for early parathyroid organogenesis. However, the regulation of parathyroid development at later stages is not well understood. Here we show that transcriptional activator v-maf musculoaponeurotic fibrosarcoma oncogene homologue B (MafB) is developmentally expressed in parathyroid cells after E11.5. MafB expression was lost in the parathyroid primordium of gcm2 null mice. The parathyroid glands of mafB(+/-) mice were mislocalized between the thymus and thyroid. In mafB(-/-) mice, the parathyroid did not separate from the thymus. Furthermore, in mafB(-/-) mice, PTH expression and secretion were impaired; expression levels of renal cyp27b1, one of the target genes of PTH, was decreased; and bone mineralization was reduced. We also demonstrate that although Gcm2 alone does not stimulate the PTH gene promoter, it associates with MafB to synergistically activate PTH expression. Taken together, our results suggest that MafB regulates later steps of parathyroid development, that is, separation from the thymus and migration toward the thyroid. MafB also regulates the expression of PTH in cooperation with Gcm2. (C) 2011 American Society for Bone and Mineral Research.