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. © 2013 wang et al.