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

Abstract

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.

Whole-genome sequencing reveals adaptations of hairy-footed jerboas (Dipus, Dipodidae) to diverse desert environments

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Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy

“…Loss of DMXL2 protein in patients' fibroblasts results in impaired autophagy, and modeling DMXL2 loss in murine neurons recapitulates defective autophagy and affects neurite development and synaptic connectivity (Esposito et al, 2019). While the complete loss of Dmxl2 is embryonically lethal in mice (Tata et al, 2014;Gobé et al, 2019), heterozygous Dmxl2 mice show macrocephaly and corpus callosum dysplasia, confirming the DMXL2 role in brain development (Kannan et al, 2017).…”

Genes Involved in Feed Efficiency Identified in a Meta-Analysis of Rumen Tissue from Two Populations of Beef Steers

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