NEUREGULIN-MEDIATED CELL SIGNALING DURING IMPLANTATION

描述(摘自申请者的摘要)：分子过程 在胚胎和子宫之间直接细胞间通讯的过程中 植入的定义不是很好。然而，时空上的表达 几个生长因子表明它们在复杂的细胞信号传递中的重要性 网络。这项提案的目标是确定增长因素的作用 新调节蛋白家族在胚泡和细胞信号转导中的作用 在植入过程中环绕子宫。NeuRegins是一种独特的 诱导多种异源二聚体形成的EGF生长因子家族 Erb B/EGF受体。目前已鉴定出三种不同的NeuRegin基因： NRG1、NRG2和NRG3。里斯博士和他的合作者在迪伊实验室 此前已证实，NRG1亚型，Neu分化因子(NDF)， 仅在植入部位的子宫中表达，并需要 激活的胚泡的存在。初步结果还表明，NRG3 和其他某些NRG1亚型在子宫和 植入前的胚泡，但NRG2的表达缺失。因此， 神经调节蛋白介导的细胞信号是异构体特异性的，并局限于 植入时间。需要检验的假设是，有选择性的成员 NRG生长因子家族参与胚胎-子宫细胞信号转导， 这些配体与特定的erbB以协调的方式起作用 感受器。针对这一问题，提出了三个具体目标：1) 确定代表性成员的临时和特定于细胞的表达 神经生长因子家族在小鼠胚胎和子宫中的表达 2)检查囊胚的状态 在卵巢雌激素和黄体酮影响下的活动改变 神经调节蛋白表达的调控；3)评估配体-受体 神经调节蛋白介导的胚胎和胚胎间细胞信号转导的特异性 子宫。为了实现这些目标，调查人员将进行量化 逆转录聚合酶链式反应、Northern和原位杂交、受体磷酸化和细胞 附着力研究。从这些研究中获得的结果可能会提供 关于生育力调节基本机制的重要信息 女人。

DESCRIPTION (adapted from the applicant's abstract): The molecular processes which direct cell-cell communication between the embryo and the uterus during implantation are not well defined. However, the spatio-temporal expression of several growth factors suggests their importance in an intricate cell-signaling network. The goal of this proposal is to determine the role of growth factors of the neuregulin family in cell signaling between the blastocyst and the surrounding uterus during implantation. Neuregulins are unique members of the EGF growth factor family that induce the formation of various heterodimers of the erbB/EGF receptors. Three different neuregulin genes have been identified: NRG1, NRG2, and NRG3. Dr. Reese and his collaborators in the Dey laboratory previously demonstrated that neu differentiation factor (NDF), an NRG1 isoform, is expressed in the uterus solely at the site of implantation and requires the presence of an activated blastocyst. Preliminary results also show that NRG3 and certain other NRG1 isoforms are expressed in the uterus and pre-implantation blastocyst, but that NRG2 expression is absent. Thus, neuregulin-mediated cell signaling is isoform-specific and restricted to the time of implantation. The hypothesis to be tested is that selective members of the NRG family of growth factors are involved in embryo-uterine cell signaling, and that these ligands act in a coordinated fashion with particular erbB receptors. To address this question, three specific aims are proposed: 1) determine the temporal and cell-specific expression of representative members of the neuregulin family of growth factors in the mouse embryo and uterus during the peri-implantation period; 2) examine whether the blastocyst's state of activity under the influence of ovarian estrogen and progesterone alters the regulation of neuregulin expression; and 3) evaluate ligand-receptor specificity in neuregulin-mediated cell signaling between the embryo and uterus. To accomplish these aims, the investigators will carry out quantitative RT-PCR, Northern and in-situ hybridization, receptor phosphorylation, and cell adhesion studies. Results obtained from these studies are likely to provide important information regarding the basic mechanisms of fertility regulation in women.