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

<div><p>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 <i>miR-17-92</i> cluster encodes six miRs that have been implicated in human cancers and heart development. We discovered that <i>miR-17-92</i> mutant embryos had severe craniofacial phenotypes, including incompletely penetrant CL/P and mandibular hypoplasia. Embryos that were compound mutant for <i>miR-17-92</i> and the related <i>miR-106b-25</i> cluster had completely penetrant CL/P. Expression of <i>Tbx1</i> and <i>Tbx3</i>, the DiGeorge/velo-cardio-facial (DGS) and Ulnar-mammary syndrome (UMS) disease genes, was expanded in <i>miR-17-92</i> mutant craniofacial structures. Both <i>Tbx1</i> and <i>Tbx3</i> had functional miR seed sequences that mediated gene repression. Analysis of <i>miR-17-92</i> regulatory regions uncovered conserved and functional <i>AP-2α</i> recognition elements that directed <i>miR-17-92</i> expression. Together, our data indicate that <i>miR-17-92</i> modulates expression of critical T-box transcriptional regulators during midface development and is itself a target of Bmp-signaling and the craniofacial pioneer factor <i>AP-2α</i>. Our data are the first genetic evidence that an individual miR or miR cluster is functionally important in mammalian CL/P.</p>