Molecular Mechanism of Wnt/Planar Cell Polarity Signaling

Wnt/平面极性信号的分子机制 总结 定向细胞极化作为生物体发育的一个关键特征，是组织和器官发育所必需的。 功能和体内平衡。平面电池极性（PCP）正在成为一种基本的机制， 各种形态发生过程，包括肢体中的软骨伸长、前-后（A-P）体轴 伸长，神经管闭合，体毛方向，内耳感觉毛细胞方向，左右 不对称性和轴突导向。PCP信号传导成分的突变已在 人类疾病，如B1型短指（趾）畸形、Robinow综合征、脊柱侧凸、脊柱裂和癫痫。 尽管五氯苯酚具有根本性的重要作用，但全球指导性的建立五氯苯酚的机制 诸如Wnt的线索仍然知之甚少，代表了发育和细胞研究中令人兴奋的前沿领域。 生物学Wnt/平面细胞极性（PCP）途径在进化上是保守的，并提供了必要的功能。 在形态发生过程中定向细胞骨架、细胞分裂、细胞迁移、分化 细胞之间的粘附，以及定位细胞延伸，如纤毛和轴突。然而，与广泛的 尽管对Wnt/β-catenin通路的研究较少，但PCP通路中的Wnt信号转导仍然知之甚少。的 PCP途径由核心PCP蛋白控制，包括货车Gogh（旺）、Frizzled（Fzd）和Dishevelled (Dvl)，最初在果蝇中发现。脊椎动物中的Wnt/PCP信号传导更为复杂， 五氯苯酚的功能多样性和脊椎动物特有的特征需要进行严格的遗传和生物化学研究， 自己的.核心PCP蛋白最初随机分布在细胞中，并逐渐积累在一个细胞中。 在PCP建立期间，通过全局线索指示细胞的一侧。Wnt5a是一个全局线索， 通过诱导含有旺的新型受体复合物在脊椎动物长骨软骨中建立PCP 如2（Vangl2）和Ror 2，一种脊椎动物特异性PCP组分。结果，Vangl2以磷酸化的方式被磷酸化。 Wnt5a以剂量依赖性方式和Vangl2磷酸化调节其功能。我们对Wnt的鉴定 诱导的PCP信号体和Vangl2磷酸化作为重要的读出器和转导器， Wnt/PCP信令为寻找Wnt/PCP信令级联中缺失的链路打开了一扇新的大门。我们建议 破译新的Wnt5a信号传导事件，最终导致PCP建立严格的遗传和 生物化学方法。在具体目标1中，我们将定义Vangl2的功能和规则 体内磷酸化。在具体目标2中，我们将定义Wnt5a信号被激活的分子机制。 在PCP途径中通过Vangl2转导。在具体目标3中，我们将确定其他监管 Wnt/PCP信号的组成部分。鉴于Wnt/PCP信号在许多形态发生中的基本作用， 我们的Wnt5a/PCP研究发现， 在脊椎动物中的Wnt信号将促进我们对Wnt信号在人类生物学和病理学中的理解。

Molecular Mechanism of Wnt/Planar Polarity Signaling Summary Directed cellular polarization as a key feature of organismal development is required for tissue and organ function and homeostasis. Planar Cell Polarity (PCP) is emerging as a fundamental mechanism regulating various morphogenetic processes including cartilage elongation in the limb, anterior-posterior (A-P) body axis elongation, neural tube closure, body hair orientation, orientation of inner ear sensory hair cells, left-right asymmetry and axon guidance in vertebrates. Mutations in PCP signaling components have been identified in human diseases such as brachydactyly type B1, Robinow syndrome, scoliosis, spinal bifida and epilepsy. Despite the fundamentally important roles of PCP, the mechanisms of PCP establishment by global instructive cues such as Wnts remain poorly understood and represent an exciting frontier in developmental and cell biology. The Wnt/Planar Cell Polarity (PCP) pathway is evolutionarily conserved and provides essential directional information during morphogenesis to orient cytoskeleton, cell division, cell migration, differential adhesion across cells, and to position cell extensions, such as cilia and axons. However, unlike the extensively studied Wnt/β-catenin pathway, Wnt signal transduction in the PCP pathway remains poorly understood. The PCP pathway is controlled by core PCP proteins including Van Gogh (Vang), Frizzled (Fzd) and Dishevelled (Dvl), which were originally identified in Drosophila. Wnt/PCP signaling in vertebrates is more complex and functionally diverse and vertebrate-specific features of PCP require rigorous genetic and biochemical studies of their own. The core PCP proteins are initially randomly distributed in the cell and gradually accumulate on one side of the cells instructed by global cues during PCP establishment. Wnt5a is a global cue required for establishing PCP in vertebrate long bone cartilage by inducing a novel receptor complex that contains Vang like 2 (Vangl2) and Ror2, a vertebrate specific PCP component. As a result, Vangl2 is phosphorylated in a Wnt5a dose-dependent manner and Vangl2 phosphorylation regulates its function. Our identification of Wnt induced PCP signalosome and Vangl2 phosphorylation as both an important readout and transducer of Wnt/PCP signaling opens a new door to find missing links in the Wnt/PCP signaling cascade. We propose to decipher novel Wnt5a signaling events that eventually lead to PCP establishment with rigorous genetic and biochemical approaches. In Specific Aim 1, we will define the functions and regulations of Vangl2 phosphorylation in vivo. In Specific Aim 2, we will define the molecular mechanism whereby Wnt5a signal is transduced through Vangl2 in the PCP pathway. In Specific Aim 3, we will identify additional regulatory components in Wnt/PCP signaling. Given the fundamental roles of Wnt/PCP signaling in many morphogenetic processes and identified WNT5A, VANGL and ROR2 mutations in human diseases, our studies of Wnt5a/PCP signaling in vertebrates will advance our understanding of Wnt signaling in human biology and pathology.