Molecular crosstalk between apical-basal polarity and planar cell polarity in axon guidance

神经元或神经细胞有细长的突起，称为轴突，通常将电脉冲从神经元的细胞体传导出去。这些轴突需要定位和识别它们合适的伙伴，以正确连接神经系统。为了帮助它们在发育中的胚胎中找到方向，轴突顶端有一个高度能动和敏感的结构，称为生长锥。虽然已经鉴定了一大组引导这些生长锥的分子，但介导这一过程的信号分子途径在很大程度上仍然未知。最近的研究表明，一条称为平面细胞极性（PCP）的通路在轴突导向中起着重要作用。PCP是细胞在组织平面中极化的过程，对包括神经形成在内的许多发育过程都很重要。所有上皮细胞都表现出另一种形式的极性，称为顶基（A-B）极性，这对它们的基本功能很重要。 调节A-B极性的蛋白质复合物之一被称为Scrib复合物，由3种蛋白质组成，Scribble（Scrib），Discs Large（Dlg）和Lethal giant larvae（Lgl）。最近的研究表明，PCP和A-B极性通路之间的分子相互作用表明在胚胎发育过程中具有共同的功能。我们建议调查，如果Scrib复合物提供了一个重要的分子之间的联系PCP途径和A-B极性的轴突指导在发展中的脊髓和大脑。我们将首先研究Scrib，Dlg和Lgl在发育中的大脑和脊髓中的表达模式，并将这些模式与称为Vangl 2，Frizzled 3和Celsr 3的3种PCP基因的表达模式进行比较。接下来，我们将敲低来自野生型和来自PCP基因Vangl 2的小鼠突变体的脊髓制备物和脑培养物中的Scrib、Dlg和Lgl中的每一种的表达，并且我们将使用各种标记方法来研究轴突引导中的任何导致的缺陷。 我们的研究将提供重要的见解，参与轴突指导的信号通路是必不可少的适当布线的中枢神经系统。

The neurons or nerve cells have slender projections called axons that typically conduct electrical impulses away from the neuron's cell body. These axons need to locate and recognize their appropriate partners for correct wiring of the nervous system. To help them find their way in the developing embryo, axons are tipped with a highly motile and sensitive structure called the growth cone. While a large group of molecules that guide these growth cones have been identified, the signaling molecular pathways mediating this process remain largely unknown. Recent studies have implicated an important role for a pathway called planar cell polarity (PCP) pathway in axon guidance. PCP is the process by which cells become polarized in the plane of a tissue and is important for many developmental processes including neurulation. All epithelial cells exhibit another form of polarity called apical-basal (A-B) polarity that is important for their fundamental function. One of the protein complexes that regulate A-B polarity is called the Scrib complex and is composed of 3 proteins, Scribble (Scrib), Discs Large (Dlg) and Lethal giant larvae (Lgl). Recent studies have demonstrated molecular interactions between PCP and A-B polarity pathway suggesting common functions during embryonic development. We propose to investigate if the Scrib Complex provides an essential molecular link between the PCP pathway and A-B polarity in axon guidance in the developing spinal cord and brain. We will first study the expression pattern of each of Scrib, Dlg and Lgl in the developing brain and spinal cord and compare these patterns to those of 3 PCP genes called Vangl2, Frizzled3 and Celsr3. Next, we will knockdown the expression of each of Scrib, Dlg and Lgl in spinal cord preparations and brain cultures from wild-type and from mice mutant for the PCP gene Vangl2 and we will use various labeling approaches to investigate any resulting defect in axon guidance. Our study will provide important insights into the signaling pathways involved in axon guidance that are essential for proper wiring of the central nervous system.