CCAAT/Enhancer-Binding Proteins (C/EBP)-α and -β Are Essential for Ovulation, Luteinization, and the Expression of Key Target Genes
CCAAT/Enhancer-Binding Proteins (C/EBP)-α and -β Are Essential for Ovulation, Luteinization, and the Expression of Key Target Genes
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DOI：
10.1210/me.2010-0318
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发表时间：
2011-02-01
影响因子：
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通讯作者：
Richards, JoAnne S.
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文献类型：
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作者：
Fan, Heng-Yu;Liu, Zhilin;Richards, JoAnne S.
LH激活表皮生长因子受体/RAS/ERK 1/2通路对于排卵和黄体化是必不可少的，因为Erk 1/2（gc-/-）小鼠的颗粒细胞（GC）耗竭使小鼠不育。作为ERK 1/2依赖性GC分化的介质，CCAAT/增强子结合蛋白（C/EBP）α和C/EBP β也被破坏。雌性Cebp B（gc-/-）突变小鼠，但不是Cebpa（gc-/-）小鼠，生育力低下，而Cebpa/B（gc-/-）双突变雌性不育。卵泡不能排卵，卵巢缺乏黄体，黄体细胞标记基因（Lhcgr、Prlr、Ptgfr、Cyp 11 a1和星星）缺失，血清孕酮水平低。微阵列分析在马绒毛膜促性腺激素（eCG）-人（h）CG处理的小鼠中鉴定了许多C/EBP α/β靶基因。在hCG后4小时，Cebpalb缺失细胞中改变的基因子集（19%）在Erk 1/2缺失细胞中也发生了改变;因此它们是ERK 1/2的常见效应子。在hCG后8和24小时，Cebpalb耗竭细胞中下调的其他基因包括已知的（Akr 1b 7、Runx 2、星星、Saa 3）和新的（Abcb 1b、Apln、Igfbp 4、Prlr、Ptgfr Timp 4）C/EBP靶标和黄体和血管细胞发育的效应物。Bhmt是一种控制甲硫氨酸代谢的基因，被认为只在肝脏和肾脏中表达，在野生型黄体细胞中表达很高，但在Cebpalb突变细胞中完全不存在。由于许多与血管发育潜在相关的基因在突变细胞中被抑制，C/EBP α/β似乎通过控制调节维持黄体细胞所需的广泛血管网络形成的基因来支配黄体化过程。因此，C/EBP α/β在复杂的黄素化过程中介导GC的终末分化。（分子内分泌学25：253-268，2011）
LH activation of the epidermal growth factor receptor/RAS/ERK1/2 pathway is essential for ovulation and luteinization because granulosa cell (GC) depletion of Erk1/2 (Erk1/2(gc-/-) mice) renders mice infertile. As mediators of ERK1/2-dependent GC differentiation, the CCAAT/enhancer-binding proteins, (C/EBP)alpha and C/EBP beta, were also disrupted. Female Cebpb(gc-/-) mutant mice, but not Cebpa(gc-/-) mice, were subfertile whereas Cebpa/b(gc-/-) double-mutant females were sterile. Follicles failed to ovulate, ovaries were devoid of corpora lutea, luteal cell marker genes (Lhcgr, Prlr, Ptgfr, Cyp11a1, and Star) were absent, and serum progesterone levels were low. Microarray analyses identified numerous C/EBP alpha/beta target genes in equine chorionic gonadotropin (eCG)-human (h)CG-treated mice. At 4 h post-hCG, a subset (19%) of genes altered in the Cebpalb-depleted cells was also altered in Erk1/2-depleted cells; hence they are common effectors of ERK1/2. Additional genes down-regulated in the Cebpalb-depleted cells at 8 and 24 h post-hCG include known (Akr1b7, Runx2, Star, Saa3) and novel (Abcb1b, Apln, Igfbp4, Prlr, Ptgfr Timp4) C/EBP targets and effectors of luteal and vascular cell development. Bhmt, a gene controlling methionine metabolism and thought to be expressed exclusively in liver and kidney, was high in wild-type luteal cells but totally absent in Cebpalb mutant cells. Because numerous genes potentially associated with vascular development were suppressed in the mutant cells, C/EBP alpha/beta appear to dictate the luteinization process by also controlling genes that regulate the formation of the extensive vascular network required to sustain luteal cells. Thus, C/EBP alpha/beta mediate the terminal differentiation of GCs during the complex process of luteinization. (Molecular Endocrinology 25: 253-268, 2011)