Dlx2基因过表达通过调控TGF-β信号通路参与第一鳃弓畸形发生

第一二鳃弓综合征是以第一鳃弓衍生的颌面骨组织发育异常为特征的常见病，诊治繁琐且效果欠佳，其发病机制尚未明确。Dlx2基因对第一鳃弓发育起着重要调控作用。我们前期已构建颌面部特异性过表达Dlx2的转基因小鼠，其出现第一鳃弓衍生骨组织的成骨分化障碍和形态异常如偏颌反颌。文献回顾显示Dlx2基因与TGF-β通路有密切关系，可能通过与TGF-β通路中的某些基因相互作用参与成骨分化调控。因此，本研究提出假说：Dlx2过表达通过调控TGF-β通路参与第一鳃弓畸形发生。拟利用已建动物模型，通过质谱分析和免疫共沉淀技术，确定与Dlx2转录因子相互作用的TGF-β通路基因，并在体外颅神经嵴细胞模型和人类第一二鳃弓综合征患者颌骨细胞中验证。揭示 Dlx2 过表达是否通过调控TGF-β信号通路参与第一鳃弓畸形发生，及其分子机制。为深入理解第一鳃弓发育畸形提供新理论，为该疾病的预防和治疗提供新的基因作用靶点。

The first arch syndromes are characterized by abnormalities of maxillofacial bones derived from the first branchial arch neural crest mesenchyme. Several distinct syndromes affecting this region of the face have been described, but the pathogenesis of most of these diseases is not yet clear. The Dlx2 homeobox transcription factor plays important roles in regulating facial bone development from the first branchial arch mesenchyme. Recent studies indicate that Dlx2 regulates the TGF-β signaling pathway, one of the most important molecular pathways in bone formation. We have successfully established a maxillofacial-specific Dlx2 over-expression transgenic mouse model. This mouse model presents osteogenic differentiation disorders in the maxillofacial bones derived from the first branchial arch. To further explore the mechanism of first arch deformity, we will perform further phenotypic analyses and use the TGF-β pathway gene microarray to identify interacting factors and downstream targets of Dlx2 in the regulation of maxillofacial bone development, and then use Co-IP analysis to verify these gene. Moreover, we will compare Dlx2 expression and osteogenic differentiation in the maxillofacial osteoblasts derived from patients with first arch syndromes and controls without the disease. These combined transgenic mouse model and human clinical studies will identify new mechanisms invovling Dlx2 and the TGF-β pathway in the pathogenesis of maxillofacial diseases. Data from this research will help development of new strategies for the prevention and treatment of maxillofacial bone disorders.