Retinoic Acid Availability Drives the Asynchronous Initiation of Spermatogonial Differentiation in the Mouse
Retinoic Acid Availability Drives the Asynchronous Initiation of Spermatogonial Differentiation in the Mouse
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DOI：
10.1095/biolreprod.110.085811
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发表时间：
2010-11-01
影响因子：
3.6
通讯作者：
Griswold, Michael D.
中科院分区：
文献类型：
--
作者：
Snyder, Elizabeth M.;Small, Christopher;Griswold, Michael D.
在大多数雄性哺乳动物的整个生殖寿命中，精子的产生是恒定的，因为精原细胞的分化受到调节。维甲酸（RA）和下游靶点Stra 8是完整精子发生所必需的。为了研究RA在启动精原细胞分化中的作用，使用了在RA反应元件控制下表达β-半乳糖苷酶的转基因小鼠模型。通过β-半乳糖苷酶活性观察新生睾丸中进行活性RA信号传导的细胞，确定RA与分化之间的关系，并证明RA降解酶在调节RA中的作用。发现β-半乳糖苷酶活性主要与分化的减数分裂前生殖细胞相关，并且在整个生精小管中不均匀地分布。此外，β-半乳糖苷酶活性在减数分裂前的生殖细胞与STRA 8蛋白共定位，并诱导在生殖细胞与外源性RA治疗。RA降解酶CYP 26 B1通过免疫组织化学发现具有生殖细胞定位和小管之间的不均匀分布。用CYP 26酶抑制剂处理导致具有β-半乳糖苷酶活性和STRA 8蛋白的生殖细胞数量增加，与分化相关的基因表达增加，与未分化生殖细胞相关的基因表达减少。这些结果表明，RA在精原细胞亚群中的作用导致整个新生儿睾丸分化的不均匀起始，可能通过CYP 26酶的作用介导。因此，RA的存在可能是启动精原细胞分化的驱动因素，并可能导致精子发生的异步。
Throughout the reproductive lifespan of most male mammals, sperm production is constant because of the regulated differentiation of spermatogonia. Retinoic acid (RA) and a downstream target, Stra8, are required for complete spermatogenesis. To examine the role of RA in initiating spermatogonial differentiation, a transgenic mouse model expressing beta-galactosidase under the control of an RA response element was used. Cells in the neonatal testis undergoing active RA signaling were visualized by beta-galactosidase activity, the relationship between RA and differentiation determined, and the role of RA-degrading enzymes in regulating RA demonstrated. Beta-galactosidase activity was found to be predominantly associated with differentiating, premeiotic germ cells and to be distributed nonuniformly throughout the seminiferous tubules. Additionally, beta-galactosidase activity in premeiotic germ cells colocalized with STRA8 protein and was induced in germ cells with exogenous RA treatment. The RA-degrading enzyme, CYP26B1, was found to have germ cell localization and nonuniform distribution between tubules via immunohistochemistry. Treatment with a CYP26 enzyme inhibitor resulted in an increased number of germ cells with both beta-galactosidase activity and STRA8 protein and an increase in the expression of genes associated with differentiation and reduced expression of a gene associated with undifferentiated germ cells. These results show the action of RA in a subset of spermatogonia leads to nonuniform initiation of differentiation throughout the neonatal testis, potentially mediated through the action of CYP26 enzymes. Thus, the presence of RA is a likely driving factor in the initiation of spermatogonial differentiation and may result in asynchronous spermatogenesis.