Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice

Abstract

β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility.

Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis

“…92 The establishment of mouse strains with deletions of one or more β-defensin family members will facilitate studies that determine their biological relevance within the urinary tract. 93,94 Ribonuclease A superfamily Four lineages of the Ribonuclease (RNase) A super family encode peptides that are associated with host defence: eosinophil-produced RNases; angiogenins; RNase 6; RNase 7 and its close relative RNase 8. 95-97 RNase 6 and RNase 7 exhibit potent antimicrobial activity against common Gram-positive and Gram-negative uropathogens; 97-99 however, the mechanisms for the antimicrobial properties of these AMPS are not completely defined.…”

Structural modeling and mRNA expression of epididymal β‐defensins in GnRH immunized boars: A model for secondary hypogonadism in man

“…In mice, the homozygous deletion of chromosome 8 β‐defensins (DefbΔ9) results in alterations in intracellular calcium, inappropriate spontaneous acrosome reaction, and marked male infertility (Y.S. Zhou et al, ). Even so, despite the highly relevant data obtained from rodent models, it is important to understand the role of β‐defensins in the epididymis of different species.…”

CRISPR/Cas9‐mediated genome editing reveals the synergistic effects of β‐defensin family members on sperm maturation in rat epididymis

“…Besides, sperm with mutational human DEFB1 (highly expressed in the corpus of the epididymis), exhibit asthenozoospermia, which has been shown to be associated with reduced sperm motility (13). Furthermore, homozygous deletion of a cluster of 9 Defb genes (DefbD9) in the mouse causes dramatically reduced sperm motility and results in male sterility (Defb15 and Defb35, expressed mainly in the caput region; Defb13 in the corpus region; and Defb1, Defb2, Defb9, Defb10, Defb11, and Defb50 in the cauda region) (14). These findings make it clear that Defb family members have important functions in sperm maturation.…”