Cellular Endocrinology Laboratory, National Institute of Immunology, New Delhi, Delhi, 110067, India.
National Institute of Animal Biotechnology, Hyderabad, India.
Cell Tissue Res. 2018 Feb;371(2):351-363. doi: 10.1007/s00441-017-2698-5. Epub 2017 Oct 24.
Testicular Sertoli cells make a niche for the division and differentiation of germ cells. Sertoli cells respond to increased follicle-stimulating hormone (FSH) and testosterone (T) levels at the onset of puberty by producing paracrine factors which affect germ cells and trigger robust onset of spermatogenesis. Such paracrine support to germ cells is absent during infancy, despite Sertoli cells being exposed to high FSH and T within the infant testis. This situation is similar to certain cases of male idiopathic infertility where post-pubertal Sertoli cells fail to support germ cell division and differentiation in spite of endogenous or exogenous hormonal support. Defective Sertoli cells in such individuals may fail to express the full complement of their paracrine repertoire. Identification and supplementation with such factors may overcome Sertoli cells deficiencies and help trigger quantitatively and qualitatively normal differentiation of germ cells. To this end, we compared the transcriptome of FSH- and T-treated infant and pubertal monkey Sertoli cells by DNA microarray. Expression of Wnt3, a morphogen of the Wnt/β-catenin pathway, was higher in pubertal Sertoli cells relative to infant Sertoli cells. Transgenic mice were generated by us in which Wnt3 expression was curtailed specifically in post-pubertal Sertoli cells by shRNA. Subfertility and oligozoospermia were noticed in such animals with low Wnt3 expression in post-pubertal Sertoli cells along with diminished expression of Connexin43, a gap-junctional molecule essential for germ cell development. We report that the FSH- and T-targetedf Wnt3 governs Sertoli cell-mediated regulation of spermatogenesis and hence is crucial for fertility.
睾丸支持细胞为生殖细胞的分裂和分化提供小生境。支持细胞在青春期开始时，通过产生旁分泌因子来响应滤泡刺激素（FSH）和睾酮（T）水平的升高，这些因子影响生殖细胞并引发强烈的精子发生。尽管婴儿睾丸中的支持细胞暴露于高 FSH 和 T 下，但在婴儿期，这种对生殖细胞的旁分泌支持是不存在的。这种情况类似于某些男性特发性不育症的情况，即青春期后支持细胞尽管存在内源性或外源性激素支持，但仍无法支持生殖细胞的分裂和分化。在这些个体中，有缺陷的支持细胞可能无法表达其旁分泌库的全部成分。鉴定和补充这些因子可能克服支持细胞的缺陷，并有助于触发生殖细胞数量和质量正常的分化。为此，我们通过 DNA 微阵列比较了 FSH 和 T 处理的婴儿和青春期猴子支持细胞的转录组。Wnt/β-连环蛋白途径的形态发生因子 Wnt3 的表达在青春期支持细胞中高于婴儿期支持细胞。我们通过短发夹 RNA 特异性地在青春期后支持细胞中敲低 Wnt3 表达，生成了转基因小鼠。在这些动物中，Wnt3 表达在青春期后支持细胞中降低，伴随着连接子 43 的表达减少，后者是生殖细胞发育所必需的间隙连接分子。我们报告说，FSH 和 T 靶向的 Wnt3 调节支持细胞介导的精子发生，因此对生育能力至关重要。
