NEUREGULIN-MEDIATED CELL SIGNALING DURING IMPLANTATION

描述（改编自申请人的摘要）：分子过程 在胚胎发育过程中， 植入没有很好地定义。然而， 几种生长因子表明它们在复杂的细胞信号传导中的重要性， 网络本提案的目标是确定生长因子的作用 神经调节蛋白家族在胚泡和胚泡之间的细胞信号传导中的作用 在子宫周围植入。神经调节蛋白是神经调节蛋白的独特成员。 EGF生长因子家族诱导多种异源二聚体的形成 EGF/erbB受体已经鉴定了三种不同的神经调节蛋白基因： NRG 1、NRG 2和NRG 3。里斯博士和他在戴伊实验室的合作者 先前证明neu分化因子（NDF），一种NRG 1同种型， 仅在子宫着床部位表达， 存在激活的胚泡。初步结果还表明，NRG 3 和某些其他NRG 1同种型在子宫中表达， 植入前囊胚，但NRG 2表达缺失。因此，在本发明中， 神经调节蛋白介导的细胞信号传导是同种型特异性的，并限于 植入时间。有待检验的假设是， 生长因子的NRG家族参与胚胎-子宫细胞信号传导， 这些配体与特定的erbB以协调的方式起作用 受体。为了解决这个问题，提出了三个具体目标：1） 确定代表性成员的时间和细胞特异性表达 神经调节蛋白家族的生长因子在小鼠胚胎和子宫 在围着床期; 2）检查囊胚的状态是否 在卵巢雌激素和孕激素的影响下， 神经调节蛋白表达的调节;和3）评估配体-受体 在胚胎和胚胎之间神经调节蛋白介导的细胞信号传导的特异性 子宫为了实现这些目标，研究人员将进行定量研究。 RT-PCR、北方和原位杂交、受体磷酸化和细胞 粘附研究。从这些研究中获得的结果可能会提供 关于生育率调节基本机制的重要信息， 妇女

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.