| First Author | Nelson ER | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 10 | Pages | e25847 |
| PubMed ID | 22022457 | Mgi Jnum | J:179587 |
| Mgi Id | MGI:5302735 | Doi | 10.1371/journal.pone.0025847 |
| Citation | Nelson ER, et al. (2011) Role of GSK-3beta in the osteogenic differentiation of palatal mesenchyme. PLoS One 6(10):e25847 |
| abstractText | INTRODUCTION: The function of Glycogen Synthase Kinases 3beta (GSK-3beta) has previously been shown to be necessary for normal secondary palate development. Using GSK-3ss null mouse embryos, we examine the potential coordinate roles of Wnt and Hedgehog signaling on palatal ossification. METHODS: Palates were harvested from GSK-3beta, embryonic days 15.0-18.5 (e15.0-e18.5), and e15.5 Indian Hedgehog (Ihh) null embryos, and their wild-type littermates. The phenotype of GSK-3beta null embryos was analyzed with skeletal whole mount and pentachrome stains. Spatiotemporal regulation of osteogenic gene expression, in addition to Wnt and Hedgehog signaling activity, were examined in vivo on GSK-3beta and Ihh +/+ and -/- e15.5 embryos using in situ hybridization and immunohistochemistry. To corroborate these results, expression of the same molecular targets were assessed by qRT-PCR of e15.5 palates, or e13.5 palate cultures treated with both Wnt and Hedgehog agonists and anatagonists. RESULTS: GSK-3beta null embryos displayed a 48 percent decrease (*p<0.05) in palatine bone formation compared to wild-type littermates. GSK-3beta null embryos also exhibited decreased osteogenic gene expression that was associated with increased Wnt and decreased Hedgehog signaling. e13.5 palate culture studies demonstrated that Wnt signaling negatively regulates both osteogenic gene expression and Hedgehog signaling activity, while inhibition of Wnt signaling augments both osteogenic gene expression and Hedgehog signaling activity. In addition, no differences in Wnt signaling activity were noted in Ihh null embryos, suggesting that canonical Wnt may be upstream of Hedgehog in secondary palate development. Lastly, we found that GSK-3beta -/- palate cultures were "rescued" with the Wnt inhibitor, Dkk-1. CONCLUSIONS: Here, we identify a critical role for GSK-3beta in palatogenesis through its direct regulation of canonical Wnt signaling. These findings shed light on critical developmental pathways involved in palatogenesis and may lead to novel molecular targets to prevent cleft palate formation. |
