MicroRNA-17-92, a direct Ap-2α transcriptional target, modulates T-box factor activity in orofacial clefting.
Among the most common human congenital anomalies, cleft lip and palate (CL/P) affects up to 1 in 700 live births. MicroRNA (miR)s are small, non-coding RNAs that repress gene expression post-transcriptionally. The miR-17-92 cluster encodes six miRs that have been implicated in human cancers and heart development. We discovered that miR-17-92 mutant embryos had severe craniofacial phenotypes, including incompletely penetrant CL/P and mandibular hypoplasia. Embryos that were compound mutant for miR-17-92 and the related miR-106b-25 cluster had completely penetrant CL/P. Expression of Tbx1 and Tbx3, the DiGeorge/velo-cardio-facial (DGS) and Ulnar-mammary syndrome (UMS) disease genes, was expanded in miR-17-92 mutant craniofacial structures. Both Tbx1 and Tbx3 had functional miR seed sequences that mediated gene repression. Analysis of miR-17-92 regulatory regions uncovered conserved and functional AP-2α recognition elements that directed miR-17-92 expression. Together, our data indicate that miR-17-92 modulates expression of critical T-box transcriptional regulators during midface development and is itself a target of Bmp-signaling and the craniofacial pioneer factor AP-2α. Our data are the first genetic evidence that an individual miR or miR cluster is functionally important in mammalian CL/P.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
Jun
J
Wang
Yan
Y
Bai
Hong
H
Li
Stephanie B
SB
Greene
Elzbieta
E
Klysik
Wei
W
Yu
Robert J
RJ
Schwartz
Trevor J
TJ
Williams
James F
JF
Martin
D000818:Animals; D001483:Base Sequence; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000235:genetics* / Q000378:metabolism
C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D020825:T-Box Domain Proteins; D050656:Transcription Factor AP-2