Dual role of DMXL2 in olfactory information transmission and the first wave of spermatogenesis

摘要

Gonad differentiation is a crucial step conditioning the future fertility of individuals and most of the master genes involved in this process have been investigated in detail. However, transcriptomic analyses of developing gonads from different animal models have revealed that hundreds of genes present sexually dimorphic expression patterns. DMXL2 was one of these genes and its function in mammalian gonads was unknown. We therefore investigated the phenotypes of total and gonad-specific Dmxl2 knockout mouse lines. The total loss-of-function of Dmxl2 was lethal in neonates, with death occurring within 12 hours of birth. Dmxl2 -knockout neonates were weak and did not feed. They also presented defects of olfactory information transmission and severe hypoglycemia, suggesting that their premature death might be due to global neuronal and/or metabolic deficiencies. Dmxl2 expression in the gonads increased after birth, during follicle formation in females and spermatogenesis in males. DMXL2 was detected in both the supporting and germinal cells of both sexes. As Dmxl2 loss-of-function was lethal, only limited investigations of the gonads of Dmxl2 KO pups were possible. They revealed no major defects at birth. The gonadal function of Dmxl2 was then assessed by conditional deletions of the gene in gonadal supporting cells, germinal cells, or both. Conditional Dmxl2 ablation in the gonads did not impair fertility in males or females. By contrast, male mice with Dmxl2 deletions, either throughout the testes or exclusively in germ cells, presented a subtle testicular phenotype during the first wave of spermatogenesis that was clearly detectable at puberty. Indeed, Dmxl2 loss-of-function throughout the testes or in germ cells only, led to sperm counts more than 60% lower than normal and defective seminiferous tubule architecture. Transcriptomic and immunohistochemichal analyses on these abnormal testes revealed a deregulation of Sertoli cell phagocytic activity related to germ cell apoptosis augmentation. In conclusion, we show that Dmxl2 exerts its principal function in the testes at the onset of puberty, although its absence does not compromise male fertility in mice. Author summary DMXL2 gene dysfunction underlies various human diseases, including breast cancer, non-syndromic hearing loss, and polyendocrine-polyneuropathy syndrome, demonstrating the large range of potential actions of DMXL2. We show here that Dmxl2 expression is crucial for survival in mice, as neonates die within hours of birth when this gene is inactivated. The transmission of olfactory information is affected, leading to an absence of suckling and impaired feeding. Severe hypoglycemia is also observed in male neonates. We observed Dmxl2 expression in several organs, including the brain, heart and adrenal glands, potentially corresponding to some of the phenotypes observed in Dmxl2 -deficient pups. We also described Dmxl2 expression in the reproductive tracts and gonads and showed that Dmxl2 inactivation specifically in the testes has a significant effect on the initial waves of spermatogenesis, resulting in very low levels of sperm production at puberty. Our results suggest that DMXL2 deficits should be considered in men with impaired fertility, as pathogenic variants of this gene may be associated with male infertility in humans.