Genetic dissection of signaling network during mammalian secondary palate development and cleft palate
Jixiang Ding
University of Louisville Birth Defects Center, USA
: Forensic Toxicol Pharmacol 2015, 4:3
Abstract
Cleft palate is a common birth defect that affects approximately 1:700 births. Palate formation during embryonic development is a complex process involving a series of steps such as vertical growth of palate shelf, palate re-orientation or elevation to horizontal level and horizontal growth until meet and fusion along the facial midline. Each step is under strict regulation to avoid possible developmental disruption and cleft palate. In this study, we used genetic approaches to investigate the functions and interactions of major signaling pathways during mouse secondary palate development and cleft palate. Zeb1 encodes a transcription modulator that regulates the activities of SHH and TGF- β signaling pathways. Genetic inactivation of the Zeb1 gene causes cleft palate due to delayed palate re-orientation/elevation. By examining the re-orientation process in Zeb1 mutant line, we found that palate re-orientation is initiated by cell migration and outgrowth from the side of vertical palate shelf. Considering the critical role of FGFs in controlling embryonic cell migration and movement, we investigated the function of FGF8 in palate re-orientation by tissue specific deletion of Fgf8 gene in palate mesenchymal cells and disclosed varied cleft palate phenotype associated with defects in palate re-orientation including vertical palate and shortened horizontal palate. In addition, we found that FGF8 carries out its role in palate development by interacting with WNT, another important signaling pathway. Since ZEB1 is a TGF- β modulator, we re-visited the issue of TGF- β 1, 2 in palate and found that Tgf- β 1 and Tgf- β 2 double mutants display cleft palates in strain dependent manner.
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