Inhibition Of Smoothened Receptor By Vismodegib Lead To Micrognathia During Embryogenesis

Background: Mandibular is an important part of craniofacial.Mandibular development is complex and multiple signaling pathways involved in the regulation of the mandibular development.These signaling pathways has a complex regulatory mechanism and regulate mandibular growth.The function of hedgehog signaling has previously been shown to be crucial for mandibular arch development.Objective: There is little report about micrognathia model using exogenous inhibitors.we utilizing Vismodegib(a small-molecule hedgehog pathway inhibitor)to mouse embryos and establish a mouse model of micrognathia and further elucidate the mechanism of micrognathia and explore the capacity for micrognathia.Methods: Pregnant ICR mice in the test group were administered 150mg/kg vismodegib(GDC-0449)by oral gavage at E10.5,the control group exposed to 0.5% methyl cellulose with 0.2% Tween at same time points.We detected whether micrognathia appears in test and control group at E11.5-E18.5 embryos using stereomicroscope.Embryos of test and control groups were collected at E16.5 for Aniline blue staining,Micro-CT.Embryos of test and control groups were collected at E11.5,E12.5,E13.5,for histology,immunohistochemical staining and TUNEL.Embryos of test and control groups were collected at E10.5+6h and analyzed SHH、PTCH1、GLi1、MSX1、SOX9、FGF8、β-catenin by q PCR.Results:In this study,we show that antagonist of the smoothened receptor(SMO)lead to micrognathia.We show that antagonist of SMO lead to the condensations and differentiation of chondrocytes delayed during the development of Meckel’s cartilage.Furthermore,we show that antagonist of SMO results in decreased cell proliferation and increased mesenchymal cell death in mandibular.Conclusions: Our results show that SMO is necessary for the survival and proliferation of mesenchymal cell during the development of mandible,and is required for the subsequent condensations and differentiation of chondrocytes to form Meckel’s cartilage,and suggests a key role in the outgrowth shape of mandibular.