Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice

TAR DNA binding protein of 43 kDa (TDP-43; gene name: Tardbp), a ubiquitously expressed evolutionarily conserved protein, is highly expressed in the preleptotene and pachytene spermatocytes. TDP-43 is linked to several human neurodegenerative disorders. Exploring its functional requirement for spermatogenesis for the first time, we show here that conditional knockout (cKO) of Tardbp in male germ cells of mice leads to failure of meiosis and arrest of spermatogenesis. Fertility trials indicated severe subfertility. Spermatocytes of cKO mice showed failure to complete prophase I of meiosis with arrest at mid-pachytene stage. 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 loss of function of TDP-43. In order to identify putative direct genes of TDP-43, we performed RNA-seq using testes from postnatal day 12 (PND12) wild type (control) and cKO (experimental) mice. Overall design: mRNA profiles of 12 day-old (PND12) Tardbp conditional knockout (cKO) and control (WT) mice