MiRNA-17-92 cluster is required for the embryonic development of Langerhans cells and dendritic epidermal T cells

Abstract

Abstract Mouse epidermis contains two major immune cells, antigen presenting Langerhans cells (LCs) and dendritic epidermal T cells (DETCs), which regulate skin immunity and involve in disease pathogenesis. Recent lineage-tracing studies have uncovered that mouse DETCs and LCs are derived from embryonic yolk-sac-derived hematopoietic precursors and self-maintain after birth. However, detailed regulating mechanisms related to their ontogeny and homeostasis remain unclear. MicroRNAs (miRNAs) are important post transcriptional regulators of protein-coding genes. Using a CSF1R-cre-mediated Dicer deletion mouse model, we found the critical involvement of miRNAs in the ontogeny of both LCs and DETCs. To further investigate the role of individual miRNAs in the ontogeny of LCs and DETCs, we evaluated the expression of miRNAs in the precursors of LCs and DETCs at different embryonic developmental stages and identified that miR17-92 cluster was highly expressed and dynamically regulated. We next generated a Csf1rCre-mediated miR17-92 deletion mouse model (miR17-92 KO) and found that conditionally deletion of miR17-92 led to significantly reduced number and interrupted phenotypes of epidermis LC and DETC precursors at E18.5 and P0 of miR17-92 KO embryos. Defective LC precursors were also identified at E14.5 and E16.5 embryonic skin, while diminished number and blocked maturation of Vg3+ DETC precursors were identified in the thymus of the same embryonic stages in miR17-92 KO mice. Overall, our results indicate that miR17-92 serves as a key epigenetic regulator in the ontogeny of LCs and DETCs. Detailed molecular mechanisms underlining the miR17-92 mediated LC and DETC developmental regulation are currently under investigation.