Laboratory of Molecular and Developmental Biology, Graduate School of Biological Science, Nara Institute of Science and Technology, Ikoma, Japan.
J Bone Miner Res. 2011 Oct;26(10):2463-72. doi: 10.1002/jbmr.458.
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 primordium 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.
血清钙和磷的动态平衡是由甲状旁腺激素（PTH）调节的，PTH 由甲状旁腺分泌。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（Gcm2）的表达始于原基的背侧/前侧，在胚胎第 9.5 天（E9.5）开始，指定甲状旁腺域。甲状旁腺原基然后与胸腺原基分离，并通过 E15.5 迁移到其成年位置在甲状腺旁边。Gcm2 基因缺失导致小鼠甲状旁腺缺失，表明 Gcm2 是早期甲状旁腺器官发生所必需的。然而，后期甲状旁腺发育的调节尚不清楚。在这里，我们表明转录激活剂 v-maf 肌肉关节纤维肉瘤癌基因同源物 B（MafB）在 E11.5 后在甲状旁腺细胞中发育表达。在 gcm2 缺失小鼠的甲状旁腺原基中，MafB 表达丢失。MafB(+/-)小鼠的甲状旁腺在胸腺和甲状腺之间错位。在 mafB(-/-)小鼠中，甲状旁腺没有与胸腺分离。此外，在 mafB(-/-)小鼠中，PTH 的表达和分泌受损；PTH 的靶基因之一肾 Cyp27b1 的表达水平降低；骨矿化减少。我们还证明，尽管 Gcm2 本身不能刺激 PTH 基因启动子，但它与 MafB 结合以协同激活 PTH 表达。总之，我们的结果表明 MafB 调节甲状旁腺发育的后期步骤，即与胸腺分离和向甲状腺迁移。MafB 还与 Gcm2 合作调节 PTH 的表达。
