During female germline development, oocytes become ahighly specialized cell type and form a maternal cytoplasmic store of crucial factors. Oocyte growth is triggered at the transition from primordial toprimary follicle and is accompanied by dynamic changes in gene expression, but the gene regulatory network that controls oocyte growth remains unknown.
在雌性生殖系發育過程中，卵母細胞成為一種高度特化的細胞類型，並形成母體細胞質儲存的關鍵因子。卵母細胞的生長是在原始卵泡向初級卵泡的轉變中觸發的，並伴隨著基因表達的動態變化，但控制卵母細胞生長的基因調控網絡仍不清楚。
Here we identify a set of transcription factors that are sufficient to trigger oocyte growth. By investigation of the changes in gene expression and functional screening using an in vitro mouse oocyte development system, we identified eight transcription factors, each of which was essential for the transition from primordial to primary follicle. Notably,enforced expression of these transcription factors swiftly converted pluripotent stem cells into oocyte-like cells that were competent forfertilization and subsequent cleavage.
在這裡，我們確定了一組轉錄因子，足以觸發卵母細胞生長。通過對小鼠體外卵母細胞發育系統中基因表達變化的研究和功能篩選，我們鑑定了8個轉錄因子，每個轉錄因子都是從原始卵泡向初級卵泡轉化所必需的。值得注意的是，這些轉錄因子的強制表達迅速地將多能幹細胞轉化為能夠進行受精和卵裂的卵母細胞樣細胞。
In mouse germline, primordial germ cells (PGCs) go through a sequential differentiation process beginning with PGC specification,followed by migration to the gonad, epigenetic reprogramming (including genome-wide DNA demethylation), fate determination and sex determination. After sex determination, female PGCs enter meiosis, thereby becoming oocytes. Oocytes are arrested in the diplotene stage of meiotic prophase I and most are maintained in primordial follicles. Cytoplasmic expansion is triggered after activation of primordial follicles. Once oocyte growth is triggered, maternal RNAs and proteins are stored in the cytoplasm. Meiosis resumes in full-grown oocytes, establishing metaphase II (MII) oocytes, and is not completed until after fertilization.
在小鼠生殖系中，原始生殖細胞（PGC）經歷了一個順序分化過程，從PGC開始，然後遷移到性腺，表觀遺傳重編程（包括全基因組DNA去甲基化），命運決定和性別決定。在性別決定之後，雌性PGCs進行減數分裂，從而成為卵母細胞。卵母細胞阻滯在減數分裂前期Ⅰ的二倍體階段，大部分在原始卵泡中。細胞質擴張是在原始卵泡激活後觸發的。一旦啟動卵母細胞生長，母體RNA和蛋白質就會儲存在細胞質中。成熟卵母細胞恢復減數分裂，成為中期Ⅱ（MII）卵母細胞，直到受精後整個減數分裂才完成。
Oocyte differentiation therefore entails two key processes: oocyte growth and meiosis. Although concurrent, these two features are separable, as evidenced by a seminal study in which STRA8-knockout mice were shown to develop oocyte-like cells that do not enter meiosis. Several genes essential for early oocyte growth have been identified, including Figla,Sohlh1, Sohlh2, Lhx8, Nobox, Taf4b, Yy1 and Tbpl2.
因此，卵母細胞分化需要兩個關鍵過程：卵母細胞生長和減數分裂。儘管這兩個特徵是同時存在的，但這兩個特徵是可分離的，正如一項開創性的研究所證明的，STRA8基因敲除小鼠被證明發育出不進入減數分裂的卵母細胞樣細胞。一些對早期卵母細胞生長至關重要的基因已經被鑑定，包括Figla、Sohlh1、Sohlh2、Lhx8、Nobox、Taf4b、Yy1和Tbpl2。
Transcriptome analysis using oocytes lacking these genes and identification of direct target sequences or genes has revealed downstream gene cascades involved in early oocyte growth. In addition, a previous microarray analysis uncovered highly dynamic gene expression changes between postnatal day 2 (P2) oocytes in primordial follicles and P6 oocytes in the primary follicles (primordial-to-primary-follicle transition (PPT)). Genes enriched at PPT were involved in protein synthesis and transcription,suggesting a role in oocyte growth.
利用缺乏這些基因的卵母細胞進行轉錄組分析，通過直接鑑定靶序列或基因，揭示了參與卵母細胞生長早期的下遊基因級聯。此外，之前的微陣列分析揭示了出生後第2天（P2）原始卵泡中的卵母細胞和P6初級卵泡（原始卵泡向初級卵泡過渡（PPT））中的卵母細胞之間高度動態的基因表達變化。在PPT中富集的基因參與蛋白質合成和轉錄，提示其在卵母細胞生長中起作用。
詞彙
oocytes
卵母細胞;初級卵母細胞;卵子;卵細胞
transcription factors
反式作用因子;轉錄因子;轉譯因子;基因轉錄因子
pluripotent stem cells
多功能幹細胞
germline
種系;生殖系;生殖細胞系;胚系基因;基因治療生殖細胞
gonad
性腺;睪丸;卵巢
transcriptome
轉錄組;轉錄組學
postnatal
出生後的；產後的
原文選自 Nature 589, 264–269 (2021).
https://doi.org/10.1038/s41586-020-3027-9