WRP AS A CANDIDATE MENTAL RETARDATION ASSOCIATED GENE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 精神发育迟滞(MR)影响2-3%的总人口。越来越清楚的是，Rho-GTP酶对肌动蛋白细胞骨架的信号在中枢神经系统的发育中起着核心作用。Rho-GTP酶(共22个基因)受大量的Rho鸟嘌呤核苷酸交换因子(GEF；85个基因)和Rho调控 GTP酶激活蛋白(GAP；70个基因)。最近的研究发现，这一途径的成员是受MR影响的潜在基因，其中一个这样的MR基因是波相关RAC-GAP蛋白(WRP)，它最初是我们发现的与RAC效应蛋白WAVE-1结合的神经元间隙。WRP是四个神经元间隙(WRP、WRP2、WRP3和RhoGAP-C1)家族的成员，这些间隙被认为是调节皮质轴突引导的。 树突棘的迁移和发育。 目的：检测WRP-GAP家族成员WRP和WRP2在体内对中枢神经系统发育的调节作用。我们将通过分析我们最近开发的一种新的WRP缺失小鼠品系来测试WRP在MR中的可能作用。在与杜克活体显微镜中心的合作下，我们将对WRP基因缺失小鼠的大脑进行形态计量分析。将对各种大脑结构进行面积测量和形状分析，与野生型小鼠进行比较，类似于最近对卷轴老鼠模型进行的测量和形状分析(Badea，A.等人，NeuroImage 2007)。这项分析将特别检查侧脑室体积，因为我们的初步数据表明，在WRP缺失的小鼠模型中，侧脑室体积可能会扩大。这些数据将 补充培养神经元和组织学的平行研究，以量化单个神经元的形态和极性。与William Wetsel博士合作对WRP缺失的小鼠进行的行为研究将直接检验WRP在认知功能中的作用。第二种基因敲除小鼠目前正在制造 WRP2。这种GAP蛋白被认为调节皮层的板层发育，可能是通过调节径向迁移过程中神经元的肌动蛋白动态来实现的。磁共振显微镜也将用于对这些小鼠进行形态计量分析，类似于上面概述的研究。上述研究的综合结果将对我们进一步了解可能与智力低下有关的分子、遗传和发育机制产生重要的积极影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mental retardation (MR) affects 2-3% of the general population. It is increasingly clear that signaling to the actin cytoskeleton by Rho-GTPases plays a central role in the development of the CNS. Rho-GTPases (numbered at 22 genes) are regulated by a large number of Rho Guanine Nucleotide Exchange Factors (GEFs; 85 genes) and Rho GTPase Activating Proteins (GAPs; 70 genes). Recent studies have identified members of this pathway as potential genes affected in MR. One such MR gene is WAVE Associated Rac-GAP Protein (WRP), which we originally discovered as a neuronal GAP that binds the Rac effector protein, WAVE-1. WRP is a member of a family of four neuronal GAPs (WRP, WRP2, WRP3, and RhoGAP-C1) that are proposed to regulate axonal guidance, cortical migration, and development of dendritic spines. Aim: Test the in vivo function of WRP GAP family members WRP and WRP2 in regulating central nervous system development. We will test the possible role of WRP in MR by analyzing a new line of WRP null mice we have recently developed. In collaboration with the Duke Center for In Vivo Microscopy we will conduct morphometric analysis of brains from WRP null mice. Area measurements and shape analysis will be performed for a variety of brain structures compared to wildtype littermates similar to that recently conducted for the Reeler mouse model (Badea, A., et.al., Neuroimage 2007). This analysis will especially examine lateral ventricle volume since our preliminary data suggests these may be dilated in the WRP null mouse model. These data will complement parrallel studies of cultured neurons and histology to quantify the morphology and polarity of individual neurons. Behavioral studies of WRP null mice done in collaboration with Dr. William Wetsel will directly examine the role of WRP in cognitive functioning. A second line of knockout mice is currently being made for WRP2. This GAP protein is thought to regulate the laminar development of the cortex, possibly by regulating the actin dynamics of neurons during radial migration. Magnetic resonance microscopy will also be used the perform morphometric analysis of these mice, similar to the study outlined above. The combined results from the above study will have an important positive impact by furthering our understanding of the molecular, genetic, and developmental mechanisms that may be involved in mental retardation.