Leucine-rich Repeat Protein LRRC37A Acts as a Molecular Scaffold Coordinating IAM-PT-NE Complex Assembly and Sperm Head Morphogenesis

<title>Abstract</title> <p> 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 <italic>Lrrc37a</italic> knockout ( <italic>Lrrc37a</italic> ^−/− ) 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, <italic>Lrrc37a</italic> ^−/− 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 <italic>LRRC37A</italic> as a candidate pathogenic gene for teratozoospermia and globozoospermia. </p>