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MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis
Johann K Eberhart1, Xinjun He, Mary E Swartz
1Institute of Neuroscience, 1254 University of Oregon, Eugene, Oregon 97403, USA. eberhart@uoneuro.uoregon.edu
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.
Insights
MicroRNA 140 (Mirn140) regulates platelet-derived growth factor (Pdgf) signaling, crucial for palate development. Disruption leads to facial defects, including cleft palate, by affecting neural crest cell migration.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Craniofacial abnormalities like cleft palate can arise from disrupted signaling pathways, including sonic hedgehog (Shh) and platelet-derived growth factor (Pdgf).
- The specific role of microRNAs in regulating palatogenesis (palate development) remains largely unexplored.
Purpose of the Study:
- To investigate the function of microRNAs in zebrafish palatogenesis.
- To elucidate the mechanism by which microRNA 140 (Mirn140) influences palate development and its connection to Pdgf signaling.
Main Methods:
- Analysis of zebrafish mutants and Mirn140-injected embryos to observe craniofacial defects.
- Identification of a Mirn140 binding site within the 3' UTR of the Pdgf receptor alpha (pdgfra) gene.
- Assessment of gene expression (pitx2, shha) and neural crest cell behavior in response to Mirn140 modulation.
Main Results:
- Mirn140 negatively regulates Pdgf signaling by binding to the pdgfra 3' UTR, controlling Pdgfra protein levels in vivo.
- pdgfra mutants and Mirn140-injected embryos exhibited similar facial defects, including cleft cartilages in the palate.
- Mirn140 modulated the attraction of cranial neural crest cells to the oral ectoderm, impacting gene expression essential for palate formation.
Conclusions:
- The interaction between Mirn140 and pdgfra represents a conserved regulatory mechanism in palatogenesis.
- Dysregulation of this Mirn140-pdgfra axis can lead to cleft palate, identifying potential candidate genes for this condition.
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