Browsing by Subject "hematopoietic phenotype"

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    The mirn23a and mirn23b microrna clusters are necessary for proper hematopoietic progenitor cell production and differentiation
    (Elsevier, 2018) Kurkewich, Jeffrey L.; Boucher, Austin; Klopfenstein, Nathan; Baskar, Ramdas; Kapur, Reuben; Dahl, Richard; Microbiology and Immunology, School of Medicine
    Mice deficient for microRNA (miRNA) cluster mirn23a exhibit increased B lymphopoiesis at the expense of myelopoiesis, whereas hematopoietic stem and progenitor cell (HSPC) populations are unchanged. Mammals possess a paralogous mirn23b gene that can give rise to three mature miRNAs (miR-23b, miR-24-1, and miR-27b) that have identical seed/mRNA-targeting sequences to their mirn23a counterparts. To assess whether compound deletion of mirn23a and mirn23b exacerbates the hematopoietic phenotype observed in mirn23a−/− mice, we generated a compound mirn23a−/−mirn23bfl/fl:Mx1-Cre conditional knockout mouse and assayed hematopoietic development after excision of mirn23b. Loss of both genes in adult bone marrow further skewed HSPC differentiation toward B cells at the expense of myeloid cells, demonstrating a dosage-dependent effect on regulating cell differentiation. Strikingly, double-knockout (DKO) mice had decreased bone marrow cellularity with significantly decreased hematopoietic stem cell and HSPC populations, a phenotype not observed in mice deficient for mirn23a alone. Competitive transplantation assays showed decreased contribution of mirn23a−/−mirn23b−/− HSPCs to hematopoietic lineages at 6 and 12 weeks after transplantation. Defects in the proliferation of mirn23a−/−b−/− HSPCs was not observed; however, DKO cells were more apoptotic compared with both wild-type and mirn23a−/− cells. Together, our data show that complete loss of mirn23a/mirn23b miRNAs results in decreased blood production and affects lineage output in a concentration-dependent manner.