Meiotic arrest is a common cause of human male infertility, but the causes of this arrest are poorly understood. TAR 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 underlie neurodegeneration. Exploring the functional requirement for TDP-43 for spermatogenesis for the first time, we show here that conditional knockout (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 mid-pachytene stage. Staining of SYCP3 and γH2AX, markers of the meiotic synaptonemal complex and DNA damage, respectively, and Super Illumination Microscopy revealed non-homologous pairing and synapsis defects. Quantitative RT-PCR showed reduction in the expression of genes critical for prophase I of meiosis, including Spo11, Rec8, and Rad21L, as well as those involved in the retinoic acid pathway, critical for entry into meiosis. RNA-seq showed 1036 up- and 1638 downregulated genes (FDR <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.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.