title: MicroRNAs 221 and 222 regulate the undifferentiated state in mammalian male germ cells.
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.
authors.affiliation: School of Molecular Biosciences, Center for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Yang
authors.forename: Karen E
authors.initials: KE
authors.lastname: Racicot
authors.forename: Amy V
authors.initials: AV
authors.lastname: Kaucher
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Oatley
authors.forename: Jon M
authors.initials: JM
authors.lastname: Oatley
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D005434:Flow Cytometry / Q000379:methods; D005854:Germ Cells / Q000166:cytology*; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D012730:Sex Chromosomes; D013091:Spermatogenesis; D013093:Spermatogonia / Q000473:pathology; D013234:Stem Cells; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C546122:MIRN221 microRNA, mouse; C546123:MIRN222 microRNA, mouse; D035683:MicroRNAs; D014212:Tretinoin; D019009:Proto-Oncogene Proteins c-kit