Shin Yong-Hyun, Ren Yu, Suzuki Hitomi, Golnoski Kayla J, Ahn Hyo Won, Mico Vasil, Rajkovic Aleksandar
Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Experimental Animal Models for Human Disease, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
J Clin Invest. 2017 Jun 1;127(6):2106-2117. doi: 10.1172/JCI90281. Epub 2017 May 15.
Following migration of primordial germ cells to the genital ridge, oogonia undergo several rounds of mitotic division and enter meiosis at approximately E13.5. Most oocytes arrest in the dictyate (diplotene) stage of meiosis circa E18.5. The genes necessary to drive oocyte differentiation in parallel with meiosis are unknown. Here, we have investigated whether expression of spermatogenesis and oogenesis bHLH transcription factor 1 (Sohlh1) and Sohlh2 coordinates oocyte differentiation within the embryonic ovary. We found that SOHLH2 protein was expressed in the mouse germline as early as E12.5 and preceded SOHLH1 protein expression, which occurred circa E15.5. SOHLH1 protein appearance at E15.5 correlated with SOHLH2 translocation from the cytoplasm into the nucleus and was dependent on SOHLH1 expression. NOBOX oogenesis homeobox (NOBOX) and LIM homeobox protein 8 (LHX8), two important regulators of postnatal oogenesis, were coexpressed with SOHLH1. Single deficiency of Sohlh1 or Sohlh2 disrupted the expression of LHX8 and NOBOX in the embryonic gonad without affecting meiosis. Sohlh1-KO infertility was rescued by conditional expression of the Sohlh1 transgene after the onset of meiosis. However, Sohlh1 or Sohlh2 transgene expression could not rescue Sohlh2-KO infertility due to a lack of Sohlh1 or Sohlh2 expression in rescued mice. Our results indicate that Sohlh1 and Sohlh2 are essential regulators of oocyte differentiation but do not affect meiosis I.
原始生殖细胞迁移至生殖嵴后，卵原细胞经历多轮有丝分裂，并在大约胚胎第13.5天进入减数分裂。大多数卵母细胞在大约胚胎第18.5天停滞于减数分裂的双线期。与减数分裂同时驱动卵母细胞分化所需的基因尚不清楚。在此，我们研究了生精和卵子发生bHLH转录因子1（Sohlh1）和Sohlh2的表达是否协调胚胎卵巢内的卵母细胞分化。我们发现，SOHLH2蛋白早在胚胎第12.5天就在小鼠生殖系中表达，且先于大约在胚胎第15.5天出现的SOHLH1蛋白表达。SOHLH1蛋白在胚胎第15.5天的出现与SOHLH2从细胞质向细胞核的转位相关，且依赖于SOHLH1的表达。产后卵子发生的两个重要调节因子，无盒卵子发生同源盒（NOBOX）和LIM同源盒蛋白8（LHX8），与SOHLH1共表达。Sohlh1或Sohlh2单基因缺陷会破坏胚胎性腺中LHX8和NOBOX的表达，但不影响减数分裂。减数分裂开始后，通过条件性表达Sohlh1转基因挽救了Sohlh1基因敲除导致的不育。然而，由于挽救的小鼠中缺乏Sohlh1或Sohlh2表达，Sohlh1或Sohlh2转基因表达无法挽救Sohlh2基因敲除导致的不育。我们的结果表明，Sohlh1和Sohlh2是卵母细胞分化的关键调节因子，但不影响减数分裂I。
