Sperm head morphogenesis relies on tight structural coordination between the acrosome, perinuclear theca (PT) and nuclear envelope (NE), but the mechanisms governing this ternary complex remain poorly defined. Here, we demonstrate that testis-specific protein LRRC37A is essential for maintaining sperm head integrity and male fertility. Male Lrrc37a knockout ( Lrrc37a ^−/− ) mice are completely infertile, generating sperm with severe head malformations, acrosome detachment from the NE, and disorganized PT architecture. LRRC37A, which specifically localizes to the acrosome during spermiogenesis, when depleted, reduces expression and disrupts the localization of core acroplaxome proteins (ACTRT3, ACTL7A, SPACA1) and nuclear envelope protein DPY19L2, impairing assembly of the inner acrosomal membrane-perinuclear theca-nuclear envelope (IAM-PT-NE) complex. Furthermore, Lrrc37a ^−/− sperm exhibit impaired motility, elevated DNA fragmentation and aberrant PLCZ1 localization, causing low fertilization rates and embryonic arrest following IVF and ICSI. Collectively, LRRC37A functions as an acrosome-resident scaffold coordinating crosstalk among organelles, cytoskeleton and the nuclear envelope to drive sperm head morphogenesis. This work sheds light on the mechanisms underlying male infertility and nominates LRRC37A as a candidate pathogenic gene for teratozoospermia and globozoospermia.

Epigenetic regulation, particularly post-translational modifications (PTMs) of histones, participates in spermatogonial stem cell (SSCs) differentiation. However, there is a lack of systemic studies of histone PTM regulation during the differentiation of SSCs due to its low number in vivo. Herein, we quantified dynamic changes of 46 different PTMs on histone H3.1 by targeted quantitative proteomics using mass spectrometry during SSCs differentiation in vitro, in combination with our RNA-seq data. We identified seven histone H3.1 modifications to be differentially regulated. In addition, we selected H3K9me2 and H3S10ph for subsequent biotinylated peptide pull-down experiments and identified 38 H3K9me2-binding proteins and 42 H3S10ph-binding proteins, which contain several transcription factors, such as GTF2E2 and SUPT5H, which appear to be crucial for epigenetic regulation of SSC differentiation.