The mirn23a and mirn23b microrna clusters are necessary for proper hematopoietic progenitor cell production and differentiation

Jeffrey L. Kurkewich, Austin Boucher, Nathan Klopfenstein, Ramdas Baskar, Reuben Kapur, Richard Dahl

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalExperimental Hematology
DOIs
StateAccepted/In press - Jan 1 2018

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Hematopoietic Stem Cells
MicroRNAs
Cell Differentiation
Knockout Mice
Transplantation
Bone Marrow
Lymphopoiesis
Myelopoiesis
Phenotype
Myeloid Cells
Population
Genes
Mammals
Seeds
B-Lymphocytes
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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The mirn23a and mirn23b microrna clusters are necessary for proper hematopoietic progenitor cell production and differentiation. / Kurkewich, Jeffrey L.; Boucher, Austin; Klopfenstein, Nathan; Baskar, Ramdas; Kapur, Reuben; Dahl, Richard.

In: Experimental Hematology, 01.01.2018.

Research output: Contribution to journalArticle

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