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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.

MicroRNA-17-92, a Direct Ap-2α Transcriptional Target, Modulates T-Box Factor Activity in Orofacial Clefting