NUDT21 regulates 3'UTR dynamics in epididymal principal cells to preserve sperm integrity

In mammals, the epididymis is composed of pseudostratified epithelium that forms the post-testicular milieu for spermatozoa. To date, the role of epithelial cells in shaping the luminal microenvironment for spermatozoa remains poorly understood. Here, we generated a conditional knockout mouse model of Nudt21 in the epididymis, the key component of mammalian cleavage factor I (CFIm) that participates in the 3'end processing of pre-mRNAs. We found that Nudt21 deletion occurred mainly in principal cells of the corpus and the cauda. The loss of NUDT21 in principal cells resulted in male infertility, owing to sperm abnormalities present in the cauda. Pseudotime analysis revealed that the differentiation of Nudt21-null principal cells was blocked, preventing them from exerting the physiological function. Amid transcripts with shortened 3’ untranslated regions (3'UTRs) after Nudt21 deletion, Dicer1 transcripts not only had shortened 3'UTR, but also skipped the exon 1, resulting in down-regulation of full length DICER1 protein. Together, these results demonstrate the essential role of NUDT21-mediated 3'UTR dynamics in preserving sperm integrity, and provide insights into the intricate communication between the epididymal epithelium and spermatozoa.