Molecular Mechanism Of Isl1 Regulating The Migration Of Tongue Myoblasts

The tongue is mainly composed of epithelium,striated muscle and mesenchyme.Abnormal tongue development can lead to many serious tongue development defects such as small tongue and tongue.Our previous study first found tongue dysplasia in Isl1 knockout mice and defects in tongue myoblast migration.In this study,we further explored the mechanism of Isl1 regulation of tongue development.We specifically knocked out the Isl1 gene in mouse mandibular epithelial cells.The defect of the migration of myoblasts in the mandible was detected in the mutant mice.The data of immune histochemistry showed that the proliferation of myoblasts decreased significantly.The RNA-Seq results showed that Shh signaling pathway was significantly inhibited,and the in situ hybridization results showed that the expression level of the chemokine SDF1 increased in the tongue primordium.Dual in vitro organ culture experiment confirmed that activation of Shh signaling pathway can inhibit the expression of SDF1.Transwell cell invasion assay further confirmed that low concentrations of SDF1 would attract myoblast migration,while high concentrations of SDF1 would repel myoblast migration.Ihh overexpressing mice?pMes-Ihh?were mated with Isl1^f/f/f and ShhCre mice to obtain ShhCre;Isl1^f/f;pMes-Ihh genotype mice,and Ihh overexpression was found to be able to partially rescue mouse tongue development defects caused by Isl1 knockout.Myoblast cells can successfully migrate to the primordia and grow out of the tongue.In summary,Isl1 indirectly regulates the expression of SDF1 by regulating Shh,and further induces the migration of tongue myoblasts.Overexpression of Ihh can partially rescue the defect of tongue development caused by the deletion of Isl1 gene.