Sohlh2 knockout mice are male-sterile because of degeneration of differentiating type A spermatogonia
Sohlh2 knockout mice are male-sterile because of degeneration of differentiating type A spermatogonia
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DOI：
10.1634/stemcells.2007-0502
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发表时间：
2008-06-01
期刊：
影响因子：
5.2
通讯作者：
Hamra, F. Kent
中科院分区：
文献类型：
--
作者：
Hao, Jing;Yamamoto, Miwako;Hamra, F. Kent
精子发生和卵子发生特异性转录因子Sohlh 2通常仅在减数分裂前生殖细胞中表达。在这项研究中，Sohlh 2和其他几个生殖细胞转录被发现诱导小鼠胚胎干细胞培养时，饲养细胞系，过度表达骨形态发生蛋白4。为了研究Sohlh 2在生殖细胞中的功能，我们产生了携带Sohlh 2无效等位基因的小鼠。雄性Sohlh 2缺陷小鼠由于精子发生受阻而不育。虽然出生前正常，但Sohlh 2基因缺失小鼠在出生后第7天的中间型和B型精原细胞数量减少。到第10天，发育到前细线期精母细胞阶段被严重破坏，使得生精小管仅具有支持细胞、未分化的精原细胞和退化的分化精原细胞集落。退化细胞类似于A2型精原细胞，并在死亡前积累在M期。在出生后第14、21、35、49、68和151天，在Sohlh 2缺失小鼠中观察到类似的表型。成年Sohlh 2基因突变小鼠的未分化A型精原细胞（DAZL+/PLZF+）与分化A型精原细胞（DAZL+/PLZF+）的比例是正常水平的2倍。在文化中，未分化的A型精原细胞Sohlh 2基因敲除小鼠分离正常增殖，但连接的突变表型异常细胞表面受体酪氨酸激酶cKit的表达。因此，Sohlh 2是A型精原细胞分化为B型精原细胞的过程所必需的。从这些研究中得出的一个结论是，睾丸因子通常通过Sohlh 2信号传导调节分化精原细胞的活力。这种调节将提供一个关键的检查点，以优化在精子发生的每个周期中进入减数分裂的精母细胞的数量。
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.