School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Biol Reprod. 2022 Jun 13;106(6):1191-1205. doi: 10.1093/biolre/ioac049.
Members of the nuclear factor I (NFI) family are key regulators of stem cell biology during development, with well-documented roles for NFIA, NFIB, and NFIX in a variety of developing tissues, including brain, muscle, and lung. Given the central role these factors play in stem cell biology, we posited that they may be pivotal for spermatogonial stem cells or further developing spermatogonia during testicular development. Surprisingly, in stark contrast to other developing organ systems where NFI members are co-expressed, these NFI family members show discrete patterns of expression within the seminiferous tubules. Sertoli cells (spermatogenic supporting cells) express NFIA, spermatocytes express NFIX, round spermatids express NFIB, and peritubular myoid cells express each of these three family members. Further analysis of NFIX expression during the cycle of the seminiferous epithelium revealed expression not in spermatogonia, as we anticipated, but in spermatocytes. These data suggested a potential role for NFIX in spermatogenesis. To investigate, we analyzed mice with constitutive deletion of Nfix (Nfix-null). Assessment of germ cells in the postnatal day 20 (P20) testes of Nfix-null mice revealed that spermatocytes initiate meiosis, but zygotene stage spermatocytes display structural defects in the synaptonemal complex, and increased instances of unrepaired DNA double-strand breaks. Many developing spermatocytes in the Nfix-null testis exhibited multinucleation. As a result of these defects, spermatogenesis is blocked at early diplotene and very few round spermatids are produced. Collectively, these novel data establish the global requirement for NFIX in correct meiotic progression during the first wave of spermatogenesis.
核因子 I（NFI）家族成员是发育过程中干细胞生物学的关键调节因子，NFIA、NFIB 和 NFIX 在多种发育组织中发挥了很好的作用，包括脑、肌肉和肺。鉴于这些因子在干细胞生物学中发挥的核心作用，我们假设它们可能对精原干细胞或睾丸发育过程中进一步发育的精原细胞至关重要。令人惊讶的是，与其他发育中的器官系统形成鲜明对比的是，这些 NFI 家族成员在曲细精管中表现出离散的表达模式。支持细胞（生精支持细胞）表达 NFIA，精母细胞表达 NFIX，圆形精子细胞表达 NFIB，而管周肌样细胞表达这三个家族成员中的每一个。进一步分析 NFIX 在生精上皮周期中的表达情况表明，它不是如我们预期的那样在精原细胞中表达，而是在精母细胞中表达。这些数据表明 NFIX 在精子发生中可能具有潜在的作用。为了研究这一点，我们分析了 Nfix （Nfix-null）基因敲除的小鼠。对 Nfix-null 小鼠出生后第 20 天（P20）睾丸中的生殖细胞进行评估，发现精母细胞开始减数分裂，但细线期精母细胞的联会复合体出现结构缺陷，未修复的 DNA 双链断裂增加。Nfix-null 睾丸中的许多发育中的精母细胞出现多核化。由于这些缺陷，减数分裂在早期双线期被阻断，很少产生圆形精子细胞。总之，这些新的数据确立了 NFIX 在第一次精子发生过程中的正确减数分裂进展中的全局需求。
