Genetic interactions between the hedgehog co-receptors Gas1 and Boc regulate cell proliferation during murine palatogenesis
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Guilherme M. Xavier1,2, Maisa Seppala1,2, Spyridon N. Papageorgiou3,4, Chen-Ming Fan5, Martyn T. Cobourne1,2
1Department of Craniofacial Development and Stem Cell Biology, King’s College London Dental Institute, Guy’s Hospital, SE1 9RT, London, UK
2Department of Orthodontics, King’s College London Dental Institute, Guy’s Hospital, SE1 9RT, London, UK
3Department of Orthodontics, School of Dentistry, University of Bonn, 53111, Bonn, Germany
4Department of Oral Technology, School of Dentistry, University of Bonn, 53111, Bonn, Germany
5Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218, USA
Keywords: Shh signaling, palatogenesis, Gas1, Boc, cleft palate
Received: August 17, 2016 Accepted: October 05, 2016 Published: November 02, 2016
Abnormal regulation of Sonic hedgehog (Shh) signaling has been described in a variety of human cancers and developmental anomalies, which highlights the essential role of this signaling molecule in cell cycle regulation and embryonic development. Gas1 and Boc are membrane co-receptors for Shh, which demonstrate overlapping domains of expression in the early face. This study aims to investigate potential interactions between these co-receptors during formation of the secondary palate. Mice with targeted mutation in Gas1 and Boc were used to generate Gas1; Boc compound mutants. The expression of key Hedgehog signaling family members was examined in detail during palatogenesis via radioactive in situ hybridization. Morphometric analysis involved computational quantification of BrdU-labeling and cell packing; whilst TUNEL staining was used to assay cell death. Ablation of Boc in a Gas1 mutant background leads to reduced Shh activity in the palatal shelves and an increase in the penetrance and severity of cleft palate, associated with failed elevation, increased proliferation and reduced cell death. Our findings suggest a dual requirement for Boc and Gas1 during early development of the palate, mediating cell cycle regulation during growth and subsequent fusion of the palatal shelves.
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