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<title>Author Summary</title> <p>During mammalian spermatogenesis, sperm with a head and a tail are formed from a round cell. This process is tightly regulated and involves the close interaction of somatic Sertoli cells and germ cells. Accumulation of the glycosphingolipid glucosylceramide in the absence of the beta-glucosidase GBA2 has been proposed to disturb sperm development, leading to morphological defects. However, the underlying mechanism is not known. Here, we demonstrate that accumulation of glucosylceramide in GBA2 knockout-mice controls the dynamics of the actin and microtubule cytoskeleton, which are crucial for sperm development. In particular, cytoskeletal structures at the interface between Sertoli and germ cells are disorganized, leading to malformation of the sperm head and a defect in acrosome formation. In summary, we provide mechanistic insights into how glucosylceramide controls cellular signaling and dysregulation of this essential glycosphingolipid leads to male infertility.</p>
