The Role of Zinc Finger Proteins During Target Gene Activation by HOM-C Proteins.

在所有后生动物中，MahaffeyHox基因编码含有同源结构域的转录因子，这些转录因子指定胚胎发生期间的体型。在果蝇中，这些基因位于触角和双胸复合体中。每个单独的HOX基因在特定的前/后结构域中表达，其中编码的蛋白通过激活一组特定的靶基因来指定区域身份。然而，不同的HOX蛋白的DNA结合特性非常相似，这导致了一种假设，即与辅因子的相互作用在HOX蛋白的靶基因选择中起着重要作用，尽管人们对辅因子的了解很少。Mahaffey实验室的最新结果表明，区域表达的锌指转录因子可能是变形(DFD)和性梳减少(SCR)HOX蛋白的辅助因子。两个多余的锌指基因缺失(DISCO)和DISCO相关基因(DISCO-r)会导致类似于DFD和SCR缺失的表型。Mahaffey博士提出，Hox和锌指蛋白之间的相互作用提供了选择和激活Hox靶基因所需的额外特异性。此外，他提出，这可能是一种保守的机制，在胚胎的其他区域和其他动物中管理身体规划规范。这一假设引出了马哈菲博士将要检验的几个预测。马哈菲博士将在果蝇体内异位共表达Disco和DFD，以确定这两种蛋白是否会导致比单独表达DFD更广泛的转化。他将研究DISCO和DFD之间分子相互作用的可能性，包括蛋白质-蛋白质和蛋白质-DNA结合研究。他还将在已知的DFD目标基因上寻找Disco/Disco-r反应元件，如果发现，他将对这些反应元件进行分子表征。为了研究这是一种保守机制的可能性，他将使用RNAi消除甲虫Tribolium的DISCO/DISCO-r功能(S)，以测试这是否会导致类似于由于失去TC-DFD和TC-SCR而观察到的同源转换。

0090040MahaffeyHox genes encode homeodomain-containing transcription factors that specify body pattern during embryogenesis in all metazoans. In the fruit fly, Drosophila melanogaster these genes are located in the Antennapedia- and Bithorax-Complexes. Each individual hox gene is expressed in a specific anterior/posterior domain wherein the encoded protein specifies regional identity through activation of a specific set of target genes. However, the DNA binding properties of the different hox proteins are quite similar This has lead to the hypothesis that interactions with cofactors play an important role in target gene selection by the hox proteins, though few cofactors are known. Recent results from the Mahaffey lab indicate that regionally-expressed zinc finger transcription factors are likely cofactors for the Deformed (Dfd) and Sex combs reduced (Scr) hox proteins. Loss of the two, redundant zinc finger genes, disconnected (disco) and disco-related (disco-r) causes a phenotype similar to loss of Dfd and Scr. Dr. Mahaffey proposed that an interaction between the hox and zinc finger proteins supplies the additional specificity that is required for selection and activation of hox target genes. Further, he proposes that this may be a conserved mechanism that governs body plan specification in other regions of the embryo and in other animals. This hypothesis leads to several predictions that Dr. Mahaffey will test. Dr. Mahaffey will ectopically co-express Disco and Dfd in Drosophila to determine whether both proteins will cause a broader transformation than that of Dfd alone. He will investigate the possibility of molecular interactions between Disco and Dfd, including protein-protein and protein-DNA binding studies. He will also search for Disco/Disco-r response elements at known Dfd target genes, and, if found, he will undertake molecular characterizations of these response elements. To examine the possibility that this is a conserved mechanism, he will use RNAi to eliminate the disco/disco-r function(s) from beetle Tribolium to test whether this causes a homeotic transformation similar to that observed due to loss of Tc-Dfd and Tc-Scr.