Houston Brendan J, Nguyen Joseph, Merriner D Jo, O'Connor Anne E, Lopes Alexandra M, Nagirnaja Liina, Friedrich Corinna, Kliesch Sabine, Tüttelmann Frank, Aston Kenneth I, Conrad Donald F, Hobbs Robin M, Dunleavy Jessica Em, O'Bryan Moira K
School of BioSciences, Bio21 Institute, The University of Melbourne, Parkville, Australia.
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
bioRxiv. 2023 Nov 13:2023.11.02.565050. doi: 10.1101/2023.11.02.565050.
Dynein complexes are large, multi-unit assemblies involved in many biological processes including male fertility via their critical roles in protein transport and axoneme motility. Previously we identified a pathogenic variant in the dynein gene in an infertile man. Subsequently we identified an additional four potentially compound heterozygous variants of unknown significance in in two additional infertile men. We thus tested the role of AXDND1 in mammalian male fertility by generating a knockout mouse model. males were sterile at all ages but could undergo one round of histologically complete spermatogenesis. Subsequently, a progressive imbalance of spermatogonial commitment to spermatogenesis over self-renewal occurred, ultimately leading to catastrophic germ cell loss, loss of blood-testis barrier patency and immune cell infiltration. Sperm produced during the first wave of spermatogenesis were immotile due to abnormal axoneme structure, including the presence of ectopic vesicles and abnormalities in outer dense fibres and microtubule doublet structures. Sperm output was additionally compromised by a severe spermiation defect and abnormal sperm individualisation. Collectively, our data highlight the essential roles of AXDND1 as a regulator of spermatogonial commitment to spermatogenesis and during the processes of spermiogenesis where it is essential for sperm tail development, release and motility.
动力蛋白复合体是大型多亚基组装体，通过在蛋白质运输和轴丝运动中的关键作用参与许多生物过程，包括男性生育能力。此前我们在一名不育男性中鉴定出动力蛋白基因的一个致病变异。随后，我们在另外两名不育男性中又鉴定出另外四个意义不明的潜在复合杂合变异。因此，我们通过构建敲除小鼠模型来测试AXDND1在哺乳动物雄性生育中的作用。AXDND1基因敲除雄性小鼠在所有年龄段均不育，但可经历一轮组织学上完整的精子发生过程。随后，精原细胞向精子发生的定向与自我更新之间出现渐进性失衡，最终导致灾难性的生殖细胞丢失、血睾屏障通透性丧失和免疫细胞浸润。在第一轮精子发生过程中产生的精子由于轴丝结构异常而无法运动，包括存在异位小泡以及外致密纤维和微管双联体结构异常。精子输出还因严重的精子释放缺陷和异常的精子个体化而受到损害。总的来说，我们的数据突出了AXDND1作为精原细胞向精子发生定向的调节因子以及在精子形成过程中的重要作用，在精子形成过程中，它对精子尾部发育、释放和运动至关重要。
