The miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic transition in developing neural stem/progenitor cells.
Neural stem/progenitor cell (NSPC) multipotency is highly regulated so that specific neural networks form during development. NSPCs cannot respond to gliogenic signals without acquiring gliogenic competence and decreasing their neurogenic competence as development proceeds. Coup-tfI and Coup-tfII are triggers of these temporal NSPC competence changes. However, the downstream effectors of Coup-tfs that mediate the neurogenic-to-gliogenic competence transition remain unknown. Here, we identified the microRNA-17/106 (miR-17/106)-p38 axis as a critical regulator of this transition. Overexpression of miR-17 inhibited the acquisition of gliogenic competence and forced stage-progressed NSPCs to regain neurogenic competence without altering the methylation status of a glial gene promoter. We also identified Mapk14 (also known as p38) as a target of miR-17/106 and found that Mapk14 inhibition restored neurogenic competence after the neurogenic phase. These results demonstrate that the miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic NSPC competence transition and that manipulation of this axis permits bidirectional control of NSPC multipotency.
Laboratory for Stem Cell Competency, Research Center for Allergy and Immunology (RCAI), RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan.
Hayato
H
Naka-Kaneda
Shiho
S
Nakamura
Mana
M
Igarashi
Hisashi
H
Aoi
Hiroaki
H
Kanki
Jun
J
Tsuyama
Shuichi
S
Tsutsumi
Hiroyuki
H
Aburatani
Takuya
T
Shimazaki
Hideyuki
H
Okano
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000737:chemistry / Q000502:physiology*; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D011401:Promoter Regions, Genetic; D017386:Sequence Homology, Amino Acid; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; D035683:MicroRNAs; C543896:Mirn106 microRNA, mouse; C543614:Mirn17 microRNA, mouse; D048051:p38 Mitogen-Activated Protein Kinases
differentiation; fate determination; glia; neural development; neurogenesis