Tomizawa Shin-Ichi, Kuroha Kazushige, Ono Michio, Nakajima Kuniko, Ohbo Kazuyuki
Department of Histology and Cell Biology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan.
Asian J Androl. 2025 Jan 1;27(1):37-43. doi: 10.4103/aja202457. Epub 2024 Aug 13.
Mouse spermatogenesis entails the maintenance and self-renewal of spermatogonial stem cells (SSCs), which require a complex web-like signaling network transduced by various cytokines. Although brain-derived neurotrophic factor (BDNF) is expressed in Sertoli cells in the testis, and its receptor tropomyosin receptor kinase B (TrkB) is expressed in the spermatogonial population containing SSCs, potential functions of BDNF for spermatogenesis have not been uncovered. Here, we generate BDNF conditional knockout mice and find that BDNF is dispensable for in vivo spermatogenesis and fertility. However, in vitro , we reveal that BDNF -deficient germline stem cells (GSCs) exhibit growth potential not only in the absence of glial cell line-derived neurotrophic factor (GDNF), a master regulator for GSC proliferation, but also in the absence of other factors, including epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and insulin. GSCs grown without these factors are prone to differentiation, yet they maintain expression of promyelocytic leukemia zinc finger ( Plzf ), an undifferentiated spermatogonial marker. Inhibition of phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and Src pathways all interfere with the growth of BDNF-deficient GSCs. Thus, our findings suggest a role for BDNF in maintaining the undifferentiated state of spermatogonia, particularly in situations where there is a shortage of growth factors.
小鼠精子发生过程涉及精原干细胞（SSCs）的维持和自我更新，这需要由多种细胞因子转导的复杂网络状信号通路。尽管脑源性神经营养因子（BDNF）在睾丸的支持细胞中表达，其受体原肌球蛋白受体激酶B（TrkB）在含有SSCs的精原细胞群体中表达，但BDNF在精子发生中的潜在功能尚未被揭示。在此，我们构建了BDNF条件性敲除小鼠，发现BDNF对于体内精子发生和生育能力并非必需。然而，在体外，我们发现BDNF缺陷的生殖系干细胞（GSCs）不仅在缺乏胶质细胞系源性神经营养因子（GDNF，GSC增殖的主要调节因子）的情况下，而且在缺乏包括表皮生长因子（EGF）、碱性成纤维细胞生长因子（bFGF）和胰岛素在内的其他因子的情况下，仍具有生长潜力。在没有这些因子的情况下生长的GSCs易于分化，但它们仍维持早幼粒细胞白血病锌指蛋白（Plzf）的表达，Plzf是未分化精原细胞的标志物。抑制磷酸肌醇3激酶（PI3K）、丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）和Src信号通路均会干扰BDNF缺陷的GSCs的生长。因此，我们的研究结果表明BDNF在维持精原细胞的未分化状态中发挥作用，特别是在生长因子短缺的情况下。
