Dakhova Olga, O'Day Diana, Kinet Noe, Yucer Nur, Wiese Mary, Shetty Gunapala, Ducy Patricia
Department of Molecular and Human Genetics, Baylor College of Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Endocrinology. 2009 Jan;150(1):404-12. doi: 10.1210/en.2008-0673. Epub 2008 Sep 25.
Dickkopf-like1 (Dkkl1) encodes a glycoprotein secreted by postmeiotic male germ cells. We report here that adult Dkkl1-deficient males have elevated sperm counts caused by a decrease in postpubertal spermatocyte apoptosis and display, upon aging, increased local production of testosterone. Molecular analyses identified the Fas death ligand (FasL) as a target for Dkkl1 pro-apoptotic activity in adult mice. Accordingly, adult FasL-deficient gld mice display an increased sperm count and decreased spermatocyte apoptosis phenotype similar to the one observed in Dkkl1-deficient mice. We also show that the elevated testosterone level observed in aging Dkkl1-deficient males is secondary to increased expression in Leydig cells of CYP11A and CYP17, two genes implicated in steroidogenesis. Furthermore, treatment of Leydig cells with Dkkl1 decreases DNA binding and transcriptional activity of steroidogenic factor 1, a pivotal regulator of gene expression in testis. Thus, this study establishes Dkkl1 as a negative regulator of adult testis homeostasis and identifies a novel, Dkkl1/FasL-dependent, regulation that specifically controls the number of postpubertal spermatocytes.
Dickkopf样蛋白1（Dkkl1）编码一种由减数分裂后雄性生殖细胞分泌的糖蛋白。我们在此报告，成年Dkkl1缺陷雄性小鼠的精子数量增加，这是由于青春期后精母细胞凋亡减少所致，并且随着年龄增长，其睾丸激素的局部产生增加。分子分析确定Fas死亡配体（FasL）是成年小鼠中Dkkl1促凋亡活性的靶点。因此，成年FasL缺陷的gld小鼠表现出精子数量增加和精母细胞凋亡减少的表型，这与在Dkkl1缺陷小鼠中观察到的表型相似。我们还表明，在衰老的Dkkl1缺陷雄性小鼠中观察到的睾丸激素水平升高是由于参与类固醇生成的两个基因CYP11A和CYP17在睾丸间质细胞中的表达增加所致。此外，用Dkkl1处理睾丸间质细胞会降低类固醇生成因子1的DNA结合和转录活性，类固醇生成因子1是睾丸基因表达的关键调节因子。因此，本研究确定Dkkl1是成年睾丸稳态的负调节因子，并确定了一种新的、依赖Dkkl1/FasL的调节机制，该机制专门控制青春期后精母细胞的数量。
