CELL SUBSTRATE INTERACTION IN CRANIOFACIAL MORPHOGENESIS

颅面形态发生中细胞基质的相互作用

• 批准号: 6634603
• 负责人: BARRY D SHUR
• 金额: $ 23.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634603
• 关键词: biological signal transduction; blocking antibody; cell adhesion molecules; cell migration; complementary DNA; craniofacial; cytoplasm; cytoskeletal proteins; cytoskeleton; embryogenesis; enzyme activity; enzyme structure; enzyme substrate; galactosyltransferases; gene expression; genetic library; genetically modified animals; histogenesis; in situ hybridization; isozymes; laboratory mouse; polymerase chain reaction; protein sequence; site directed mutagenesis; yeast two hybrid system

DESCRIPTION (adapted from the Investigator's abstract): The development of the head and neck, as well as of the embryo in general, is the result of extensive cellular migrations that form virtually all of the skeletal, muscular and glandular structures. The mechanisms that underlie the initiation, directionality and cessation of cell migrations are responsible for the most common congenital malformation, and are just now beginning to be elucidated. During the previous support period, a novel molecular mechanism for mesenchymal cell interactions with the underlying basal lamina was identified. Results show that cell surface beta1, 4-galactosyltransferase I (GT I) is expressed on the leading and trailing edges of migrating cells, where it is associated with the cytoskeleton, facilitating cell spreading and migration. Altering the expression of GT I on the cell surface positively leads to decreased cell migration, while decreased GT I expression leads to increased rates of cell migration, due to the cells becoming either overly adhesive or loosely adhesive to the basal lamina substratum. The binding site for GT I in the basal lamina has been identified as N-linked glycosides in the E8 domain of laminin. The relative degree of stability of lamellipodia can be altered by GT I association with the cytoskeleton. GT I may also catalytically release from its oligosaccharide-binding site in laminin. GTI is expressed on the growth cones of developing neurites where it facilitated neurite outgrowth. Increasing GT I expression leads to increased rates of neurite formation. GTI is expressed on the cell surface of metastatic cells, and down-regulating GT I expression or adding GT I perturbants can inhibit metastasis in vivo. Clustering of GT I by multivalent ligands induces a transient phosphorylation of FAK, leading to depolymerization of stress fibers, presumably facilitating cell migration. GT is expressed on the leading edge of migrating neural crest cells, and microinjection of anti-GT IgG inhibits the migration of neural crest cells in vivo. However, GT I-null mice have grossly normal facial development, suggesting the presence of other matrix receptors that compensate for the loss of GT I. In this renewal application, the function of the newly identified GT isoform (GT II - GT VI) during craniofacial morphogenesis will be addressed. Also, the spectrum of cytosolic proteins that associate with GT I, enabling it to function as a signal transducing receptor for glycoside ligands, will be defined.

描述（改编自研究者摘要）： 头部和颈部，以及一般的胚胎，是广泛的结果， 细胞迁移，形成几乎所有的骨骼，肌肉和 腺体结构启动的机制， 细胞迁移的方向性和停止是导致 常见的先天性畸形，刚刚开始被阐明。 在之前的支持期间，一种新的间充质细胞的分子机制， 鉴定了细胞与下面的基底层的相互作用。结果表明 细胞表面β 1，4-半乳糖基转移酶I（GT I）表达于 迁移细胞的前缘和后缘，在那里它与 细胞骨架，促进细胞扩散和迁移。改变 GT I在细胞表面的表达阳性导致细胞减少， 迁移，而GT I表达减少导致细胞迁移率增加。 迁移，由于细胞变得过度粘附或松散粘附 到基底层。基膜中GT I的结合位点 已被鉴定为层粘连蛋白E8结构域中的N-连接糖苷。的 GT I的结合可以改变板状伪足的相对稳定程度 与细胞骨架。GT I也可以催化释放其 层粘连蛋白中的寡糖结合位点。GTI在生长锥上表达 促进神经突生长的神经突。增加GT I 表达导致神经突形成速率增加。GTI表示为 转移性细胞的细胞表面，并下调GT I表达或 加入GT I干扰剂可以抑制体内转移。GT I的聚类， 多价配体诱导FAK的瞬时磷酸化，导致 应力纤维解聚，可能促进细胞迁移。GT 在迁移的神经嵴细胞的前缘表达， 微量注射抗GT IgG可抑制神经嵴细胞的迁移， vivo.然而，GT I缺失小鼠具有大体上正常的面部发育， 这表明存在其他基质受体来补偿这种损失 关于GT I在这次更新申请中，新确定的GT的功能 亚型（GT Ⅱ- GT Ⅵ）在颅面形态发生过程中的作用。 此外，与GT I相关的胞质蛋白质谱，使其能够 作为糖苷配体的信号转导受体， 定义了