A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment.
miRNA populations, including mammalian homologues of lin-4 (mir-125) and let-7, undergo a marked transition during stem-cell differentiation. Originally identified on the basis of their mutational phenotypes in stem-cell maturation, mir-125 and let-7 are strongly induced during neural differentiation of embryonic stem (ES) cells and embryocarcinoma (EC) cells. We report that embryonic neural stem (NS) cells express let-7 and mir-125, and investigate post-transcriptional mechanisms contributing to the induction of let-7. We demonstrate that the pluripotency factor Lin-28 binds the pre-let-7 RNA and inhibits processing by the Dicer ribonuclease in ES and EC cells. In NS cells, Lin-28 is downregulated by mir-125 and let-7, allowing processing of pre-let-7 to proceed. Suppression of let-7 or mir-125 activity in NS cells led to upregulation of Lin-28 and loss of pre-let-7 processing activity, suggesting that let-7, mir-125 and lin-28 participate in an autoregulatory circuit that controls miRNA processing during NS-cell commitment.
Rybak
Agnieszka
A
Institute of Cell and Neurobiology, Center for Anatomy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Fuchs
Heiko
H
Smirnova
Lena
L
Brandt
Christine
C
Pohl
Elena E
EE
Nitsch
Robert
R
Wulczyn
F Gregory
FG
D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C488352:Lin-28 protein, mouse; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D016601:RNA-Binding Proteins