Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice.
Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice.
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DOI：
10.1016/j.jbc.2021.101231
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Reddi PP
中科院分区：
文献类型：
--
作者：
Campbell KM;Xu Y;Patel C;Rayl JM;Zomer HD;Osuru HP;Pratt M;Pramoonjago P;Timken M;Miller LM;Ralph A;Storey KM;Peng Y;Drnevich J;Lagier-Tourenne C;Wong PC;Qiao H;Reddi PP
减数分裂停滞是人类男性不育的常见原因，但人们对减数分裂停滞的原因知之甚少。 43 kDa 的交互反应 DNA 结合蛋白 (TDP-43) 在减数分裂前细线期和粗线期阶段的精母细胞中高度表达。 TDP-43 与多种人类神经退行性疾病有关，其中其核清除伴随细胞质聚集是神经退行性病变的基础。首次探索 TDP-43 对精子发生的功能需求，我们在此表明，小鼠雄性生殖细胞中 Tardbp 基因（编码 TDP-43）的条件性敲除（cKO）会导致睾丸尺寸减小、生殖细胞耗竭、生精上皮内液泡形成以及精子产量减少。生育力试验也显示出严重的生育力低下。 cKO 小鼠的精母细胞未能完成减数分裂前期 I，并停滞在粗线期中期。联会复合体蛋白 3 和 γH2AX（分别是减数分裂联会复合体和 DNA 损伤的标记）的染色以及超照明显微镜揭示了非同源配对和联会缺陷。定量 RT-PCR 显示对减数分裂前期 I 至关重要的基因表达减少，包括 Spo11（减数分裂双链断裂起始子）、Rec8（减数分裂重组蛋白）和 Rad21L（RAD21 样粘连蛋白复合物成分），以及参与进入减数分裂至关重要的视黄酸途径的基因。 RNA-Seq 显示 Tardbp cKO 睾丸中有 1036 个上调基因和 1638 个下调基因（错误发现率 <0.05），影响减数分裂途径。我们的工作揭示了 TDP-43 在男性减数分裂中的关键作用，并表明在不育男性中看到的某些形式的减数分裂停滞可能是由于 TDP-43 功能丧失所致。
Meiotic arrest is a common cause of human male infertility, but the causes of this arrest are poorly understood. Transactive response DNA-binding protein of 43 kDa (TDP-43) is highly expressed in spermatocytes in the preleptotene and pachytene stages of meiosis. TDP-43 is linked to several human neurodegenerative disorders wherein its nuclear clearance accompanied by cytoplasmic aggregates underlies neurodegeneration. Exploring the functional requirement for TDP-43 for spermatogenesis for the first time, we show here that conditional KO (cKO) of the Tardbp gene (encoding TDP-43) in male germ cells of mice leads to reduced testis size, depletion of germ cells, vacuole formation within the seminiferous epithelium, and reduced sperm production. Fertility trials also indicated severe subfertility. Spermatocytes of cKO mice showed failure to complete prophase I of meiosis with arrest at the midpachytene stage. Staining of synaptonemal complex protein 3 and γH2AX, markers of the meiotic synaptonemal complex and DNA damage, respectively, and super illumination microscopy revealed nonhomologous pairing and synapsis defects. Quantitative RT–PCR showed reduction in the expression of genes critical for prophase I of meiosis, including Spo11 (initiator of meiotic double-stranded breaks), Rec8 (meiotic recombination protein), and Rad21L (RAD21-like, cohesin complex component), as well as those involved in the retinoic acid pathway critical for entry into meiosis. RNA-Seq showed 1036 upregulated and 1638 downregulated genes (false discovery rate <0.05) in the Tardbp cKO testis, impacting meiosis pathways. Our work reveals a crucial role for TDP-43 in male meiosis and suggests that some forms of meiotic arrest seen in infertile men may result from the loss of function of TDP-43.
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影响因子：
4.5
作者：
Gely-Pernot A;Raverdeau M;Teletin M;Vernet N;Féret B;Klopfenstein M;Dennefeld C;Davidson I;Benoit G;Mark M;Ghyselinck NB
通讯作者：
Ghyselinck NB
影响因子：
9.2
作者：
Chen, Dong;Zheng, Wei;Lin, Aiping;Uyhazi, Katherine;Zhao, Hongyu;Lin, Haifan
通讯作者：
Lin, Haifan
DOI：
10.3791/55378
发表时间：
2017-11-22
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Dia F;Strange T;Liang J;Hamilton J;Berkowitz KM
通讯作者：
Berkowitz KM
影响因子：
2.8
作者：
Hamer, G.;Novak, I.;Hoog, C.
通讯作者：
Hoog, C.
影响因子：
4.8
作者：
Fuentealba, Rodrigo A.;Udan, Maria;Baloh, Robert H.
通讯作者：
Baloh, Robert H.