Hao Jing, Yamamoto Miwako, Richardson Timothy E, Chapman Karen M, Denard Bray S, Hammer Robert E, Zhao Guang Quan, Hamra F Kent
Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Stem Cells. 2008 Jun;26(6):1587-97. doi: 10.1634/stemcells.2007-0502. Epub 2008 Mar 13.
The spermatogenesis and oogenesis-specific transcription factor Sohlh2 is normally expressed only in premeiotic germ cells. In this study, Sohlh2 and several other germ cell transcripts were found to be induced in mouse embryonic stem cells when cultured on a feeder cell line that overexpresses bone morphogenetic protein 4. To study the function of Sohlh2 in germ cells, we generated mice harboring null alleles of Sohlh2. Male Sohlh2-deficient mice were infertile because of a block in spermatogenesis. Although normal prior to birth, Sohlh2-null mice had reduced numbers of intermediate and type B spermatogonia by postnatal day 7. By day 10, development to the preleptotene spermatocyte stage was severely disrupted, rendering seminiferous tubules with only Sertoli cells, undifferentiated spermatogonia, and degenerating colonies of differentiating spermatogonia. Degenerating cells resembled type A2 spermatogonia and accumulated in M-phase prior to death. A similar phenotype was observed in Sohlh2-null mice on postnatal days 14, 21, 35, 49, 68, and 151. In adult Sohlh2-mutant mice, the ratio of undifferentiated type A spermatogonia (DAZL+/PLZF+) to differentiating type A spermatogonia (DAZL+/PLZF-) was twice normal levels. In culture, undifferentiated type A spermatogonia isolated from Sohlh2-null mice proliferated normally but linked the mutant phenotype to aberrant cell surface expression of the receptor-tyrosine kinase cKit. Thus, Sohlh2 is required for progression of differentiating type A spermatogonia into type B spermatogonia. One conclusion originating from these studies would be that testicular factors normally regulate the viability of differentiating spermatogonia by signaling through Sohlh2. This regulation would provide a crucial checkpoint to optimize the numbers of spermatocytes entering meiosis during each cycle of spermatogenesis. Disclosure of potential conflicts of interest is found at the end of this article.
精子发生和卵子发生特异性转录因子Sohlh2通常仅在减数分裂前的生殖细胞中表达。在本研究中，当在过表达骨形态发生蛋白4的饲养细胞系上培养时，发现Sohlh2和其他几种生殖细胞转录本在小鼠胚胎干细胞中被诱导表达。为了研究Sohlh2在生殖细胞中的功能，我们构建了携带Sohlh2无效等位基因的小鼠。雄性Sohlh2缺陷小鼠由于精子发生受阻而不育。尽管出生前正常，但到出生后第7天，Sohlh2基因敲除小鼠的中间型和B型精原细胞数量减少。到第10天，发育到细线前期精母细胞阶段严重受阻，导致生精小管中仅含有支持细胞、未分化的精原细胞以及正在分化的精原细胞的退化集落。退化细胞类似于A2型精原细胞，并在死亡前积累于M期。在出生后第14、21、35、49、68和151天的Sohlh2基因敲除小鼠中观察到了类似的表型。在成年Sohlh2突变小鼠中，未分化的A型精原细胞（DAZL+/PLZF+）与正在分化的A型精原细胞（DAZL+/PLZF-）的比例是正常水平的两倍。在培养中，从Sohlh2基因敲除小鼠分离出的未分化A型精原细胞正常增殖，但将突变表型与受体酪氨酸激酶cKit的异常细胞表面表达联系起来。因此，Sohlh2是分化型A型精原细胞向B型精原细胞进展所必需的。这些研究得出的一个结论是，睾丸因子通常通过Sohlh2发出信号来调节正在分化的精原细胞的活力。这种调节将提供一个关键的检查点，以优化每个精子发生周期中进入减数分裂的精母细胞数量。潜在利益冲突的披露见本文末尾。
