FUNCTION OF MAMMALIAN SINGLE MINDED GENES, SIM1 AND SIM2

描述(改编自调查人员摘要)：本报告的目标 建议研究哺乳动物Sim1和Sim2基因的功能 使用转基因小鼠模型。Sim1和Sim2是 果蝇模拟(单基因)基因。在飞行中，sim扮演着至关重要的角色。 在中枢神经系统的发育过程中。的初步研究 小鼠的SIM基因强烈暗示了进化上的保守功能。 SIM蛋白包含被称为PAS结构域的保守序列基序， 它由几种环境感受器蛋白共享，如二恶英 受体、低氧诱导因子、果蝇昼夜节律 调节剂PER和枯草杆菌产孢量调节剂KEATE。这 有信息强烈表明，SIMs也可能对特定的 环境信号通过它们的PAS域。这项建议包括 目的如下：1)记录Sim1和Sim2的表达模式 2)建立Sim1、Sim2基因功能缺失的小鼠模型 同源重组和突变表型鉴定 评估这些基因的正常功能，以及3)识别可能的小 调节Sim1和Sim2功能的分子配体。重要的是 小鼠Sim2基因定位于人类唐氏综合征的同系型 区域。此外，缺乏Sim1的突变小鼠表现出神经性 可能与多发性硬化症有关的疾病。探索和 可能调控Sim1和Sim2的小分子配体的鉴定 函数将是开发方法以更改其 体内的基因活性。

DESCRIPTION (adapted from investigator's abstract): The goal of this proposal is to investigate the function of mammalian Sim1 and Sim2 genes using transgenic mouse models. Sim1 and Sim2 are homologues of the Drosophila sim (singleminded) gene. In the fly, sim plays essential roles in the development of the central nervous system. Preliminary studies of the mouse Sim genes strongly suggest evolutionarily conserved functions. The SIM proteins contain conserved sequence motif termed the PAS domain, which is hared by several environmental sensor proteins such as the Dioxin receptor, the Hypoxia Inducible Factor, the Drosophila circadian rhythm regulator Per, and the B. subtilis sporulation regulator KinA. This information strongly indicated that SIMs may also respond to specific environmental signals via their PAS domains. This proposal includes the following aims: 1) documenting the expression patterns of Sim1 and Sim2 in detail; 2) establishing mouse models lacking Sim1 and Sim2 gene function by homologous recombination and characterizing mutant phenotypes in order to assess the normal function of these genes, and 3) identifying possible small molecule ligands that modulate the function of Sim1 and Sim2. Importantly, the mouse Sim2 gene is located in the syntenic human Down syndrome critical region. Furthermore, mutant mice lacking Sim1 display neurological disorders that may relate to multiple sclerosis. Exploration and identification of possible small ligands that regulate Sim1 and Sim2 function will be the first step towards developing methods to alter their gene activities in vivo.