Genetic Analysis of ErbB2 in Mammalian Development

描述(申请人提供)：该项目的长期目标是阐明erbB2调控哺乳动物发育的机制。ErbB信号网络已经被建立为包括突触发育在内的多种发育和生理过程的关键调节因子。ERBB2是表皮生长因子受体(EGFR或ErbB1)家族的成员，该家族还包括erB3和ERBB4。ErbB2、ErB3和ErBB4受体的异构化是NRG信号转导的关键。突触发育中的核心问题之一是如何通过正负向信号来塑造突触前终末和突触后装置，以确保每个突触后装置都与特定的神经末梢紧密相对。那些没有对立的人被负面信号驱散了。NRG1-ErbB受体信号通路是调节突触分化的重要途径。我们至少要面对三个问题，才能理解erbB2和其他erbB受体在哺乳动物发育中的作用。首先，erbB2在多种细胞类型中表达，这对几个器官和神经元结构的正常发育和功能是必不可少的。ERBB2可能在每种细胞类型中发挥不同的功能。第二，在整个胚胎和出生后发育过程中，erbB2蛋白表达的时间和模式决定了erbB2的不同生理作用。第三，在erbB受体之间存在功能冗余，这取决于erbB受体和细胞环境的互补。此外，最近的研究结果表明，共同定位于突触部位的CDK5及其靶底物中间丝蛋白Nestin是NRG1-erbB受体途径的下游分子，调节突触分化。在目前的提案中，我们将结合条件突变小鼠遗传学、解剖学、细胞、分子和生化方法来阐明erbB2和erbB4在神经发育中的作用。目的1确定erbB2/ERBB4-&GT；-CDK5通路在NRG1调控的突触发育中的作用。目的2确定Nestin在NMJ发育和NRG1诱导的AChR簇分散中的作用。目的3阐明Nestin通过NRG1与公共卫生相关来调节AChR簇稳定性的机制。进一步了解由erbB受体介导的NRG信号的细胞和分子机制，不仅可以促进我们对几个器官、神经和神经内分泌系统的发育的了解，而且还可能为人类疾病的生物学提供见解，包括神经退行性疾病、感觉和运动神经疾病、心脏疾病和乳腺癌。这一信号通路最近被认为与精神分裂症等人类疾病有关。

DESCRIPTION (provided by applicant): The long-term goal of this project is to elucidate the mechanisms by which erbB2 regulates mammalian development. The erbB signaling network has been established as a key regulator of multiple developmental and physiological processes, including synaptic development. ErbB2 is a member of the epidermal growth factor receptor (EGFR or erbB1) family that also includes erbB3 and erbB4. Receptor heterodimerization of erbB2, erbB3 and erbB4 is essential for NRG signaling. One of central questions in synaptic development is how positive and negative signals to sculpt both presynaptic terminals and postsynaptic apparatus to ensure that each postsynaptic apparatus is closely apposed by a specialized nerve terminal. Those that are not apposed are dispersed by the negative signals. NRG1-ErbB receptor signaling has emerged as an essential pathway to modulate synaptic differentiation. There are at least three issues with which we are confronted to understand the role of erbB2 and other erbB receptors in mammalian development. First, erbB2 is expressed in multiple cell types, which are essential for the proper development and function of several organs and neuronal structures. ErbB2 may play distinct functions in each of cell types. Second, the distinct physiological roles of erbB2 are based on the timing and patterns of erbB2 protein expression throughout embryonic and postnatal development. Third, there is functional redundancy among erbB receptors, depending on the compliment of the erbB receptors and cellular context. Furthermore, recently results suggest that Cdk5 and its target substrate intermediate filament protein nestin both of which are co-localized at synaptic sites, are the downstream molecules of the NRG1-erbB receptor pathway to regulate synaptic differentiation. In the present proposal, we will combine conditional mutation mouse genetics, anatomical, cellular, molecular, and biochemical approaches to elucidate the role of erbB2 and erbB4 in neural development. Aim 1 is to determine the role of the erbB2/erbB4->-Cdk5 pathway in NRG1-regulated synaptic development. Aim 2 is to determine the role of nestin in NMJ development and in NRG 1-induced dispersion of AChR clusters. Aim 3 is to elucidate the mechanisms by which nestin modulates the stability of AChR clusters by NRG1 Public health relevance. Further understanding of the cellular and molecular mechanisms underlying NRG signaling mediated by the erbB receptors not only advances our knowledge of the development of several organs, neural and neuroendocine systems but may also provide insights into the biology of human diseases, including neurodegenerative diseases, sensory and motor neuropathies, cardiac diseases and breast cancer. This signaling pathway has been recently implicated in human disorders such as schizophrenia.