PAX6 downregulates miR-124 expression to promote cell migration during embryonic stem cell differentiation.
PAX6-null mice exhibit defects in multiple organs leading to neonatal lethality, but the mechanism by which this occurs has not yet fully elucidated. In this study, we generated induced pluripotent stem cells (iPSCs) from Pax6-mutant mice and investigated the effect of PAX6 on cell fate during embryoid body (EB) formation. We found that PAX6 promotes cell migration by directly downregulating miR-124, which is important for the fate transition of migratory cells during gastrulation of embryonic stem (ES) cells. Although several downstream targets of miR-124 have been reported, little is known regarding the upstream regulation of miR-124. When we observed EB formation of iPSCs from Pax6-mutant mice, we found that higher levels of miR-124 in Pax6 homozygous EBs (Homo-EBs) inhibited cell migration, whereas inhibition of miR-124 in Homo-EBs rescued the migratory phenotypes associated with PAX6 deficiency. Further, we found that PAX6 binds to the promoter regions of the miR-124-3 gene and directly represses its expression. Therefore, we propose a novel PAX6-miR-124 pathway that controls ES cell migration. Our findings may provide important information for studies on ES cell differentiation and embryonic development.
1 Department of Cell Biology, Peking University Stem Cell Research Center, Peking University Health Science Center , School of Basic Medical Sciences, Beijing, China .
Jing
J
Fang
Ting
T
Zhang
Yinan
Y
Liu
Yang
Y
Li
Shixin
S
Zhou
Daijun
D
Song
Yanxia
Y
Zhao
Ruopeng
R
Feng
Xiaoyan
X
Zhang
Lingsong
L
Li
Jinhua
J
Wen
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D058732:Embryoid Bodies / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology*; D005136:Eye Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
D005136:Eye Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins