Article abstract
Nature Genetics 40, 290 - 298 (2008)
Published online: 10 February 2008 | doi:10.1038/ng.82
MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis
Johann K Eberhart1,3, Xinjun He1,3, Mary E Swartz1, Yi-Lin Yan1, Hao Song1, Taylor C Boling1, Allison K Kunerth1, Macie B Walker2, Charles B Kimmel1 & John H Postlethwait1
Abstract
Disruption of signaling pathways such as those mediated by sonic hedgehog (Shh) or platelet-derived growth factor (Pdgf) causes craniofacial abnormalities, including cleft palate. The role that microRNAs play in modulating palatogenesis, however, is completely unknown. We show that, in zebrafish, the microRNA Mirn140 negatively regulates Pdgf signaling during palatal development, and we provide a mechanism for how disruption of Pdgf signaling causes palatal clefting. The pdgf receptor alpha (pdgfra) 3' UTR contained a Mirn140 binding site functioning in the negative regulation of Pdgfra protein levels in vivo. pdgfra mutants and Mirn140-injected embryos shared a range of facial defects, including clefting of the crest-derived cartilages that develop in the roof of the larval mouth. Concomitantly, the oral ectoderm beneath where these cartilages develop lost pitx2 and shha expression. Mirn140 modulated Pdgf-mediated attraction of cranial neural crest cells to the oral ectoderm, where crest-derived signals were necessary for oral ectodermal gene expression. Mirn140 loss of function elevated Pdgfra protein levels, altered palatal shape and caused neural crest cells to accumulate around the optic stalk, a source of the ligand Pdgfaa. These results suggest that the conserved regulatory interactions of mirn140 and pdgfra define an ancient mechanism of palatogenesis, and they provide candidate genes for cleft palate.
- Institute of Neuroscience, 1254 University of Oregon, Eugene, Oregon 97403, USA.
- Present address: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.
- These authors contributed equally to this work.
Correspondence to: Johann K Eberhart1,3 e-mail: eberhart@uoneuro.uoregon.edu
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