Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2
Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2
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DOI：
10.1172/jci42021
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Thakker, Rajesh V.
中科院分区：
文献类型：
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作者：
Grigorieva, Irina V.;Mirczuk, Samantha;Thakker, Rajesh V.
编码双锌指转录因子的GATA 3杂合突变可导致甲状旁腺功能减退伴感音神经性耳聋和肾发育不良。在这里，我们研究了GATA 3在甲状旁腺功能中的作用，通过用低钙和维生素D饮食挑战GATA 3（+/-）小鼠，以暴露甲状旁腺功能的任何缺陷。这导致Gata 3（+/-）小鼠的死亡率高于Gata 3（+/+）小鼠。与野生型同窝出生的小鼠相比，Gata 3（+/-）小鼠的血浆钙和甲状旁腺激素（PTH）浓度较低，甲状旁腺较小，Ki-67增殖率降低。在EMS，Gata 3（+/-）胚胎具有较小的甲状旁腺-胸腺原基，表达甲状旁腺特异性基因胶质细胞缺失2（Gcm 2）的细胞较少，Gcm 2是人类GCMB的同源物。相比之下，E11.5 Gata 3（-/-）胚胎没有Gcm 2表达，到E12.5时，第三和第四咽囊有明显缺陷，包括甲状旁腺-胸腺原基缺失。电泳迁移率变化，荧光素酶报告，染色质免疫沉淀试验表明，GATA 3特异性结合到GCMB启动子内的功能性双GATA基序。因此，GATA 3对于甲状旁腺祖细胞的分化和存活至关重要，并且与GCM 2/B一起形成甲状旁腺发育和功能中的转录级联的一部分。
Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3(+/-) mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3(+/-) mice compared with Gata3(+/+) mice. Compared with their wild-type littermates, Gata3(+/-) mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At EMS, Gata3(+/-) embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3(-/-) embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function.