PAN2 maintains mRNA poly(A) tail homeostasis and regulates translation during spermiogenesis in mice.

The elongation and shortening of poly(A) tails are the most common types of post-transcriptional mRNA regulation in eukaryotic cells. PAN2-PAN3 and CCR4-NOT complexes are the main cytoplasmic enzymes that trim the poly(A) tails of mRNAs. However, the in vivo function of PAN2-PAN3 in mammals remains unclear. Here, we found that the germline-specific deletion of Pan2 causes male infertility due to a step-8/9 spermatogenic arrest, while meiotic prophase proceeds normally. Using PAIso-seq2 and mass spectrometry analyses, we define stage-specific remodeling of poly(A) tails that is disrupted in Pan2-null round spermatids (RS). Ribo-lite reveals a global reduction in translation efficiency in Pan2-deficient RS, correlating with proteomic changes and impairing pathways for spermatid differentiation. Endogenous IP-MS identifies PAN2 association with PABPC1 and initiation factors (EIF4E, EIF4A1, EIF5A), whose protein levels decline upon Pan2 loss, indicating compromised stability of key translational machinery. Together, these findings highlight the important physiological functions of PAN2 in spermiogenesis and expand our understanding of the post-transcriptional regulation of mRNAs in specific physiological processes.