Six1/Eya1 转录复合物在泌尿生殖道发育中的作用及其机制

As one of congenital diseases, genitourinary tract malformation has now been increasing in recent years. The pathogenic mechanism of genitourinary tract malformation is still unclear. In previous studies, we found that the deficiency of Six1 and Eya1 gene in mouse embryo resulted in the genitourinary tract morphologic abnormality, which is similar to the human genitourinary tract malformation. Thus, we hypothesize that Six1/Eya1 transcriptional complex-regulated downstream gene transcription and translation may be involved in the development of genitourinary tract, and TGF-beta/Smad4 signaling transduction may be also involved. In this project, we try to demonstrate the related mechanism of Six1/Eya1-regulated genitourinary tract development by a series of experiments and models, including Six1-/- and Eya1-/- mice, Cre/lox P sit specific DNA recombination, RNA in situ hybridization, X-gal staining, BrdU label, and iUTC. These studies will provide us new targets for the early genetic diagnosis and treatment of genitourinary tract malformation.

泌尿生殖道畸形是临床最常见的严重危害儿童健康的先天性疾病之一，近年来其发病率逐年上升,原因不明。目前，人们对泌尿生殖道畸形的致病机制尚不清楚，在前期研究中，我们发现缺失Six1 和Eya1 基因的小鼠胚胎出现泌尿生殖道形态异常，与人类泌尿生殖道畸形极为相似。我们推测泌尿生殖道的发育与Six1/Eya1 转录复合物调节下游有关基因转录翻译有关，并需要TGF?/Smad4 信号转导分子的参与。我们拟采用Six1 和Eya1 双基因敲除小鼠模型，运用Cre/loxP 位点特异性DNA 重组策略、RNA 原位杂交、X-gal 染色、BrdU标记、iUTC 等手段对上述假设予以验证，探讨Six1/Eya1 调控泌尿生殖道发育的相关机制，为泌尿生殖道畸形的早期基因诊断和治疗提供新的靶点。

泌尿生殖道畸形是临床最常见的严重危害儿童健康的先天性疾病之一。我们采用Six1 和Eya1 双基因敲除小鼠模型，运用Cre/loxP 位点特异性DNA 重组策略、RNA 原位杂交、X-gal 染色、BrdU标记、iUTC 等手段予以验证，探讨了Six1/Eya1 调控泌尿生殖道发育的相关机制，从而揭示泌尿生殖道发育的分子调控机制，为临床泌尿生殖道畸形的遗传咨询、早期基因诊断提供新的靶点，为防治泌尿生殖道畸形提供理论和实验依据。相关研究结果发表论文1篇，培养研究生4人，另一篇文章正在投稿中。研究过程中我们发现了 Six1 和Smad4的协同作用在泌尿生殖道发育过程并不是十分明显，同时意外地发现Wnt 信号通路起着至关重要的作用，下一步我们将对这一现象进行深入研究。