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

作者：Wang Jun^*; Bai Yan; Li Hong; Greene Stephanie B; Klysik Elzbieta; Yu Wei; Schwartz Robert J; Williams Trevor J; Martin James F

来源：PLoS Genetics, 2013, 9(9): e1003785.

DOI：10.1371/journal.pgen.1003785

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-2 alpha 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-2 alpha. Our data are the first genetic evidence that an individual miR or miR cluster is functionally important in mammalian CL/P.

• 出版日期2013-9