Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy.
Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy.
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DOI：
10.1038/srep20193
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发表时间：
2016-02-02
影响因子：
4.6
通讯作者：
Singh RN
中科院分区：
文献类型：
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作者：
Ottesen EW;Howell MD;Singh NN;Seo J;Whitley EM;Singh RN
脊髓性肌萎缩症（SMA）是由运动神经元存活蛋白（SMN）水平低下引起的，SMN是高等真核生物必需的多功能蛋白。虽然SMN是与神经变性相关的最受关注的蛋白质之一，但其在脊椎动物中的性别特异性作用仍然未知。我们利用轻度SMA模型（C/C模型）来研究低SMN对哺乳动物性器官生长和发育的影响。我们发现C/C男性睾丸发育受损，曲细精管退化，精子数量减少和生育力低下，但C/C女性没有明显的性器官表型。强调了SMN表达的需求增加，野生型睾丸显示出极高水平的SMN蛋白相比，其他组织。我们的结果显示，对C/C雄性生殖器官发育和功能至关重要的途径受到严重干扰，包括类固醇生物合成、细胞凋亡和精子发生。与C/C睾丸生精小管中细胞凋亡增强一致，我们记录到DNA片段化细胞急剧增加。SMN在成人C/C睾丸中由于成人特异性剪接开关而以高水平表达，但在早期睾丸发育期间不能补偿低水平。我们的研究结果揭示了SMA疾病进展的新特征，并将SMN与一般男性不育症联系起来。
Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN), a multifunctional protein essential for higher eukaryotes. While SMN is one of the most scrutinized proteins associated with neurodegeneration, its gender-specific role in vertebrates remains unknown. We utilized a mild SMA model (C/C model) to examine the impact of low SMN on growth and development of mammalian sex organs. We show impaired testis development, degenerated seminiferous tubules, reduced sperm count and low fertility in C/C males, but no overt sex organ phenotype in C/C females. Underscoring an increased requirement for SMN expression, wild type testis showed extremely high levels of SMN protein compared to other tissues. Our results revealed severe perturbations in pathways critical to C/C male reproductive organ development and function, including steroid biosynthesis, apoptosis, and spermatogenesis. Consistent with enhanced apoptosis in seminiferous tubules of C/C testes, we recorded a drastic increase in cells with DNA fragmentation. SMN was expressed at high levels in adult C/C testis due to an adult-specific splicing switch, but could not compensate for low levels during early testicular development. Our findings uncover novel hallmarks of SMA disease progression and link SMN to general male infertility.