Abstract
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.
Highlights
The evidence that there is a genetic component underlying CL/ P is compelling
Genome wide association studies (GWAS) and mouse genetics studies have pointed to genes and genomic regions that are associated with cleft lip and palate (CL/P) [3], [4]
Results miR-17-92 mutant embryos have orofacial clefting We found that miR-17-92 mutant embryos had severe craniofacial defects including CL/P and mandibular hypoplasia with notching, revealing that miR-17-92 is a critical regulator of craniofacial development (Figure 1A–H, Figure S1)
Summary
Analysis of a Danish cohort of CL/P cases revealed that relatives of patients with CL/P have a higher relative risk for CL/P compared to background risk levels. This notion of CL/P heritability is supported by twin studies [1], [2]. Genome wide association studies (GWAS) and mouse genetics studies have pointed to genes and genomic regions that are associated with CL/P [3], [4]. MiR-17-92 is found in an amplified region associated with small cell lung cancer, as well as in B-cell lymphomas, and is over-expressed in several solid tumor types, including breast, colon, lung, pancreas, and prostate cancers [7]
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