HnRNPGT knockout disrupts pre-mRNA splicing and arrests sperm development prior to meiotic metaphase

Human male infertility has long been associated with genetic defects that affect nuclear RNA binding proteins, yet what RNA targets these proteins control or why their absence causes infertility remain poorly defined. Here we find that genetic knockout of the mouse nuclear RNA binding protein gene Hnrnpgt causes azoospermia. Knockout male germ cells arrest during the highly transcriptionally active stage of meiotic prophase with altered meiotic nuclear RNA processing patterns. Hnrnpgt knockout most notably leads to the inclusion of previously unidentified cryptic exons that could otherwise disable gene function and poison the meiotic transcriptome. Hnrnpgt target genes include Esco1 and Kdm4d, which encode proteins that are important for chromosome function, and Hnrnpgt null germ cells have altered centromere clustering and H3K9me3 distribution patterns. Our data reveal a nuclear RNA processing programme that is critical for meiotic metaphase entry. Overall design: Gene expression profiling by RNA-Seq of mouse testes 18 days post-partum. Samples from C57BL/6 background, either wild type (n=3) or HnRNPGT Cre-Lox knockout (n=3).

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Ehrmann I, Crichton JH, Gazzara MR, James K, Liu Y, Grellscheid SN, Curk T, de Rooij D, Steyn JS, Cockell S, Adams IR, Barash Y, Elliott DJ