Bellessort, B. | bioRxiv Science

bioRxiv2022

Distal-less homeobox genes Dlx5/6 regulate Mulllerian duct regression

Dlx5 and Dlx6 encode distal-less homeodomain transcription factors that are present in the genome as a linked pair at a single locus. Dlx5 and Dlx6 have redundant roles in craniofacial, skeletal, and uterine development. Previously, we performed a transcriptome comparison for anti-Mullerian hormone (AMH)-induced genes expressed in the Mullerian duct mesenchyme of male and female mouse embryos. In that study, we found that Dlx5 transcripts were nearly seven-fold higher in males compared to females and Dlx6 transcripts were found only in males, suggesting they may be AMH-induced genes. Therefore, we investigated the role of Dlx5 and Dlx6 during AMH-induced Mullerian duct regression. We found that Dlx5 was detected in the male Mullerian duct mesenchyme from E14.5 to E16.5. In contrast, in female embryos Dlx5 was detected in the Mullerian duct epithelium. Dlx6 expression in Mullerian duct mesenchyme was restricted to males. Dlx6 expression was not detected in female Mullerian duct mesenchyme or epithelium. Genetic experiments showed that AMH signaling is necessary for Dlx5 and Dlx6 expression. Mullerian duct regression was variable in Dlx5 homozygous mutant males at E16.5, ranging from regression like controls to a block in Mullerian duct regression. In E16.5 Dlx6 homozygous mutants, Mullerian duct tissue persisted primarily in the region adjacent to the testes. In Dlx5-6 double homozygous mutant males Mullerian duct regression was also found to be incomplete but more severe than either single mutant. These studies suggest that Dlx5 and Dlx6 act redundantly to mediate AMH-induced Mullerian duct regression during male differentiation.

developmental biology↗

bioRxiv2018

Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain

CapsuleComparative analysis of gene expression signatures from endometriosis and mouse models shows that CACNA2{delta}s calcium-channel components involved in nociception are targets for the treatment of endometriosis-associated pain.\n\nContextDifferential gene expression analyses comparing endometriotic lesions to eutopic endometrium have shown that the transcription factors DLX5 and DLX6 are drastically down-regulated in the ectopic implants. These finding suggests that regulatory cascades involving DLX5/6 might be involved in the origin of endometriosis symptoms such as chronic pelvic pain. We have shown that mice in which Dlx5 and Dlx6 are selectively inactivated in the uterus present an endometrial phenotype reminiscent of endometriosis implants.\n\nObjectiveIdentify new targets for the treatment of endometriosis.\n\nDesignTo better focus the search for endometriosis targets we have compared the profile of genes deregulated in normal and ectopic women endometrium to those deregulated in the uterus of normal and Dlx5/Dlx6-null mice.\n\nSettingsAcademic research unit and University Hospital research laboratory\n\nAnimalsMice carrying a uterus-specific deletion of Dlx5/Dlx6.\n\nInterventionsAnalysis of archive sections from normal endometrium and endometriosis implants.\n\nMain OutcomeA novel endometriosis signature suggests that 2{delta}s subunits of voltage-gated calcium channel are targets for the management of endometriosis-associated pain.\n\nResultsWe identify a signature of 30 genes similarly deregulated in human endometriosis implants and in Dlx5/6-null mouse uteri reinforcing the notion that the down-regulation of Dlx5/6 is an early event in the progress of endometriosis. CACNA2D3, a component of the voltage-dependent calcium channel complex is strongly overexpressed both in endometriosis implants and in mutant mouse uteri; other members of the alfa2delta family, CACNA2D1 and CACNA2D2, are also overexpressed in endometriosis.\n\nConclusionCACNA2D1, CACNA2D2 and CACNA2D3 are directly involved in pain perception. In particular, CACNA2D3 has been associated to pain sensitization and heat nociception in animal models while, in patients, variants of this gene are associated to reduced sensitivity to acute noxious stimuli. As CACNA2Ds are targets of gabapentinoids analgesics, our results suggest to consider the use of these drugs for the treatment of endometriosis-associated pain. Indeed, recent small-scale clinical studies have shown that gabapentin can be effective in the treatment of women chronic pelvic pain. Our findings reinforce the need for a large definitive trial.

pharmacology and toxicology↗