MiRNAs as the molecular clock regulating mandibular osteoinduction (921.5)

Abstract

Precise timing of cranial neural crest cell (CNCC) differentiation into bone is essential for proper formation of the craniofacial bones. Delayed osteoinduction leads to micrognathia, whereas premature osteoinduction causes craniosynostosis. To understand the etiology of these birth defects, we must uncover the molecular clock that regulates the onset of osteogenesis. CNCC autonomously control the timing of their differentiation into osteoblasts by regulating expression of Bone Morphogenetic Protein (BMP), yet how CNCC establish the timing of BMP expression remains unclear. Good candidates for intrinsic temporal control of gene expression are miRNAs, small non‐coding RNAs that target mRNAs for degradation. To identify specific miRNAs involved in mandibular osteogenesis, we performed microarray analysis on chick mandibles during the stages of osteoinduction. We identified and validated temporal expression changes in miRNAs whose targets include BMP signaling pathway members that are known to be involved in bone formation. For example, miR‐19b, which is upregulated at the start of osteogenesis, targets repressors of BMP signaling including Smurf1. Conversely, let‐7a and let‐7c, which are upregulated at the close of osteoinduction, target the BMP receptor AcvR‐2B. These results suggest that miRNAs intrinsically control the timing of CNCC osteoinduction by regulating the period of active BMP signaling.Grant Funding Source: NIH 5P30DE020750‐02