Gcm2 regulates the maintenance of parathyroid cells in adult mice

Glial cells missing homolog 2 (GCM2), a zinc finger-type transcription factor, is essential for the development of parathyroid glands. It is considered to be a master regulator because the glands do not form when Gcm2 is deficient. Remarkably, Gcm2 expression is maintained throughout the fetal stage and after birth. Considering the Gcm2 function in embryonic stages, it is predicted that Gcm2 maintains parathyroid cell differentiation and survival in adults. However, there is a lack of research regarding the function of Gcm2 in adulthood. Therefore, we analyzed Gcm2 function in adult tamoxifen-inducible Gcm2 conditional knockout mice. One month after tamoxifen injection, Gcm2-knockout mice showed no significant difference in serum calcium, phosphate, and PTH levels and in the expressions of calcium-sensing receptor (Casr) and parathyroid hormone (Pth), whereas Ki-67 positive cells were decreased and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) positive cell number did not change, as compared with those of controls. Seven months after tamoxifen injection, Gcm2-knockout mice showed shrinkage of the parathyroid glands and fewer parathyroid cells. A significant decrease was noted in Casr- and Pth-expressing cells and serum PTH and Ca levels, whereas serum phosphate levels increased, as compared with those of controls. All our results concluded that a reduction of Gcm2 expression leads to a reduction of parathyroid cell proliferation, an increase in cell death, and an attenuation of parathyroid function. Therefore, we indicate that Gcm2 plays a prominent role in adult parathyroid cell proliferation and maintenance.

神经细胞缺失同源蛋白2（Glial cells missing homolog 2, GCM2）作为一种锌指型转录因子，对甲状旁腺的发育至关重要。该蛋白被视为主控调节因子，因为当Gcm2表达缺失时，甲状旁腺无法正常形成。值得注意的是，Gcm2的表达在整个胎儿期以及出生后均持续存在。鉴于Gcm2在胚胎发育阶段的功能，有研究推测其在成年个体中同样可维持甲状旁腺细胞的分化与存活。然而目前针对成年个体中Gcm2的功能研究仍较为匮乏。因此，本研究针对他莫昔芬诱导型Gcm2条件性敲除小鼠，开展了成年个体中Gcm2功能的相关分析。在他莫昔芬注射1个月后，与对照组相比，Gcm2敲除小鼠的血清钙、磷酸盐及甲状旁腺激素（PTH）水平，以及钙敏感受体（calcium-sensing receptor, Casr）和甲状旁腺激素（Pth）的表达水平均无显著差异；但Ki-67阳性细胞数量有所减少，而末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记法（TUNEL）阳性细胞数量未发生明显变化。在他莫昔芬注射7个月后，Gcm2敲除小鼠的甲状旁腺出现萎缩，甲状旁腺细胞数量也有所减少。与对照组相比，该组小鼠中表达Casr和Pth的细胞数量显著减少，血清PTH及钙水平亦显著降低，而血清磷酸盐水平则出现升高。综合所有实验结果，本研究证实Gcm2表达降低会导致甲状旁腺细胞增殖能力下降、细胞死亡增加，并削弱甲状旁腺的功能。综上，本研究表明Gcm2在成年个体的甲状旁腺细胞增殖与功能维持中发挥着关键作用。