Study Of Roles Of Transcription Factors Six1 And Six2 In Cranial Maxillofacial Development

First and second arches play important roles in craniofacial formation.Malformation of first and second arches yield varying deformities in severity for fetus: hypoplasia conchea or absent auricle,eyes size and position defects,mandible and maxilla hypoplasia et al.We found that 1)Six1 null mutant mice share similar deformities with human patinets,2)There is remarkable similarity in coding region and binding sites for mammalian Six1 and Six2.We plan to construct Six1 /2 combine mutant mice to study their overlapping roles in mammalian craniofacial development.Objectives:1.To Study expression pattern of Six1 and Six2,uncover synergistic roles of Six1 and Six2 combine mutant mice and the underlying mechanism.2.Finding out the possible casue of first and second arch syndrome by human genome exone-sequcing.Methods:In Situ and lineage tracing were used in Six1 and Six2 patterning study.Observed the morphology of Six1 and Six2 compound mutant mice by HE staining,skeletal preparation.Figured out the possible cause of Six1 and Six2 related deformities by in situ and q PCR.Extracted patients' DNA for exone sequencing.Results:Six1 and Six2 have a partial overlaping role during craniofacial development.2.There is a dosage dependent in severity in Six1 and Six2 compound muntant mice.Six1 and Six2 modulate upper and lower jaws patterning by repressing BMP and Edn1-Dlx5/6 signaling pathway.Six1 mutation also lead to lower incisors agenesis,and got BMP and HH signaling pathway involved.3.Human genome exone-sequencing results show that couples of genes may involve in first and second arch syndromes.Conclusions:Six1 and Six2 play significant and overlapping roles during craniofacial development from E9.5.2.Six1 and Six2 mutantion can lead to dispatterning of jaws,which is dosage dependent.BMP and Edn-Dlx5/6 signaling path ways are involved in these process.Mutation of Six1 can also cause lower incisors agenesis by repressing BMP and HH pathways.3.Human syndromes have multiple genes involved,and we need to generate animal model to better understand the roles of these genes.