Persistent requirement and alteration of the key targets of PRDM1 during primordial germ cell development in mice.
Persistent requirement and alteration of the key targets of PRDM1 during primordial germ cell development in mice.
复制标题
小鼠原始生殖细胞发育过程中 PRDM1 关键靶标的持续需求和改变。
DOI：
10.1095/biolreprod.115.133256
复制
发表时间：
2015
影响因子：
3.6
通讯作者：
Saitou M.
中科院分区：
文献类型：
--
作者：
Yamashiro C;Hirota T;Kurimoto K;Nakamura T;Yabuta Y;Nagaoka SI;Ohta H;Yamamoto T;Saitou M.
原始生殖细胞（PGCs）是全能性的基础，对生殖和遗传至关重要。小鼠中的PGCs在胚胎日（E）7.0左右从外胚层产生，通过后肠内胚层迁移，并在胚胎性腺中定殖和增殖，直到E13.5左右，然后分化成卵原细胞或卵原细胞。PRDM 1是一种转录抑制因子，在PGC的特化中起着重要作用，包括强烈抑制体细胞中胚层程序。使用诱导型条件性敲除系统，我们在这里表明，PRDM 1是至关重要的整个PGC的发展。当Prdm 1在E9.5或E10.5的迁移性PGCs中缺失时，或在E11.5的雄性性腺PGCs中缺失时，PGCs分别从E10.5、E11.5或E13.5左右通过凋亡被消除。当Prdm 1在雌性生殖腺PGCs在E11.5删除，PGCs进展到第一次减数分裂前期在一个明显的正常的方式，但卵原细胞表现出异常的粗线期表型，从E16.5左右突然凋亡。一部分PGCs（约10%）从Prdm 1缺失中逃逸，足以恢复相当正常的生殖细胞池，无论是在男性还是女性成年人中。PRDM 1在迁移和/或性腺PGC中的关键靶点，包括发育、凋亡和生殖腺分化的基因，仅显示与PGC特异性的那些靶点有适度的重叠，并且富含组蛋白H3赖氨酸27三甲基化（H3 K27 me 3）。我们的研究结果提供了关键的洞察机制，保持PGC的转录完整性。
Primordial germ cells (PGCs) are the foundation of totipotency and vital for reproduction and heredity. PGCs in mice arise from the epiblast around Embryonic Day (E) 7.0, migrate through the hindgut endoderm, and colonize and proliferate in the embryonic gonads until around E13.5 prior to their differentiation either into prospermatogonia or oogonia. PRDM1, a transcriptional repressor, plays an essential role in PGC specification that includes robustly repressing a somatic mesodermal program. Using an inducible conditional knockout system, we show here that PRDM1 is critically required throughout PGC development. WhenPrdm1was deleted in migrating PGCs at E9.5 or E10.5, or in male gonadal PGCs at E11.5, PGCs were eliminated by apoptosis from around E10.5, E11.5, or E13.5, respectively. WhenPrdm1was deleted in female gonadal PGCs at E11.5, PGCs progressed into the first meiotic prophase in an apparently normal fashion, but the oogonia exhibited an aberrant pachytene phenotype, undergoing abrupt apoptosis from around E16.5. The escape of a fraction of PGCs (∼10%) from thePrdm1deletion was sufficient to recover fairly normal germ cell pools, both in male and female adults. The key targets of PRDM1 in migrating and/or gonadal PGCs, including genes for development, apoptosis, and prospermatogonial differentiation, showed only a modest overlap with those upon PGC specification, and were enriched with histone H3 lysine 27 trimethylation (H3K27me3). Our findings provide critical insight into the mechanism for maintaining the transcriptional integrity of PGCs.