MicroRNAs 221 and 222 regulate the undifferentiated state in mammalian male germ cells

Development. 2013 Jan 15;140(2):280-90. doi: 10.1242/dev.087403. Epub 2012 Dec 5.

Abstract

Continuity of cycling cell lineages relies on the activities of undifferentiated stem cell-containing subpopulations. Transition to a differentiating state must occur periodically in a fraction of the population to supply mature cells, coincident with maintenance of the undifferentiated state in others to sustain a foundational stem cell pool. At present, molecular mechanisms regulating these activities are poorly defined for most cell lineages. Spermatogenesis is a model process that is supported by an undifferentiated spermatogonial population and transition to a differentiating state involves attained expression of the KIT receptor. We found that impaired function of the X chromosome-clustered microRNAs 221 and 222 (miR-221/222) in mouse undifferentiated spermatogonia induces transition from a KIT(-) to a KIT(+) state and loss of stem cell capacity to regenerate spermatogenesis. Both Kit mRNA and KIT protein abundance are influenced by miR-221/222 function in spermatogonia. Growth factors that promote maintenance of undifferentiated spermatogonia upregulate miR-221/222 expression; whereas exposure to retinoic acid, an inducer of spermatogonial differentiation, downregulates miR-221/222 abundance. Furthermore, undifferentiated spermatogonia overexpressing miR-221/222 are resistant to retinoic acid-induced transition to a KIT(+) state and are incapable of differentiation in vivo. These findings indicate that miR-221/222 plays a crucial role in maintaining the undifferentiated state of mammalian spermatogonia through repression of KIT expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Flow Cytometry / methods
  • Germ Cells / cytology*
  • Humans
  • In Situ Hybridization
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Sex Chromosomes
  • Spermatogenesis
  • Spermatogonia / pathology
  • Stem Cells
  • Tretinoin / pharmacology

Substances

  • Intercellular Signaling Peptides and Proteins
  • MIRN221 microRNA, mouse
  • MIRN222 microRNA, mouse
  • MicroRNAs
  • Tretinoin
  • Proto-Oncogene Proteins c-kit