Genetic interactions between the hedgehog co-receptorsGas1andBocregulate cell proliferation during murine palatogenesis

Abstract

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.

Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice

“…It has been suggested that SHH signaling pathway effectors may be involved in GC differentiation as well [ 19 , 20 ]. The SHH receptor Patched 1 (PTCH1), together with the co-receptors CDON (Codon), BOC (Brother of Codon), and GAS1, functions as a control switch that turns on SHH signal transduction [ 20 , 21 , 22 ]. Upon SHH binding to its receptors, PTCH1-mediated inhibition of SMO (Smoothened; a G-coupled transmembrane receptor) is lifted, allowing constitutive SMO activity and associated downstream signaling [ 23 ].…”