CELL SUBSTRATE INTERACTION IN CRANIOFACIAL MORPHOGENESIS

头部和颈部的发育，以及整个胚胎的发育， 是复杂的细胞迁移的结果，这些迁移实际上形成了 骨骼、肌肉和腺体结构的全部。这一机制 这是细胞的启动、定向和终止的基础 人们对迁徙知之甚少，尽管事实是 对一些最常见的先天性畸形负有责任。 在过去的几年里，我的实验室发现了一种新的分子 间充质细胞与底层基底细胞相互作用的机制 片层基质。结果表明，细胞表面B1，4-半乳糖基转移酶 (Ga1Tase)参与间充质细胞的扩散和迁移 层粘连蛋白。GalTase通过间接免疫荧光定位于 迁移细胞的前沿和尾部边缘，与其 建议在传播和迁徙过程中发挥作用。GalTase不会 参与与层粘连蛋白的初始黏附，这是由 不同的层粘连蛋白受体，以及层粘连蛋白中的结合位置 经鉴定为E8结构域，并已显示出E8‘S的生物活性 至少部分依赖于与表面GalTase的结合。表面 GalTase与GalTase的特异性相关联。那个表面GalTase 可能在细胞迁移过程中起催化作用，而不是作为 凝集素，表现为层粘连蛋白基质的自发半乳糖化 通过迁移小鼠成纤维细胞。以类似的方式，GalTase是 在发育中的神经突起的生长锥体上表达，在那里它介导 层粘连蛋白上突起和突起的生长。近几年来的研究进展 表面半乳糖酶的分子生物学现在允许一个人增加或 减少表面GalTase的表达，从而导致可预测 对片状脂肪形成、细胞迁移和轴突的影响 在层粘连蛋白上生长。最后，表面GalTase似乎在 体内，如由抗半乳糖酶抗体的能力所显示的抑制 神经脊细胞在体内的迁移。这些研究定义了一部小说 层粘连蛋白细胞突起形成的分子机制。 这些结果导致了下一系列的具体目标，我们将 在即将到来的资助期内继续努力，这分为两大类 类别：GalTase与细胞骨架和 体内形态发生过程中表面半乳糖酶功能的分析。

The development of the head and neck, as well as the embryo in general, is the result of sophisticated cellular migrations that form virtually ll of the skeletal, muscular and glandular structures. The mechanism that underlie the initiation, directionality and cessation of cell migrations are poorly understood, despite the fact that they are responsible for some of the most common congenital malformations. During the past few years, my laboratory has identified a novel molecular mechanism for mesenchymal cell interactions with the underlying basal lamina matrix. Results show that cell surface B1,4-galactosyltransferase (Ga1Tase) participate during mesenchymal cell spreading and migration on laminin. GalTase is localized by indirect immunofluorescence to the leading and trailing edges of migrating cells, consistent with its proposed role during spreading and migration. GalTase does not participate during initial adhesion to laminin, which is mediated by distinct laminin receptors, and binding site in laminin has been identified as the E8 domain, and E8's biological activity has been shown to be at least partly dependent upon binding to surface GalTase. Surface GalTase associates with the specific for GalTase. That surface GalTase may function catalytically during cell migration, rather than as a lectin, is shown by the spontaneous galactosylation of laminin matrices by migrating mouse fibroblasts. In an analogous manner, GalTase is expressed on the growth cone of developing neurites, where it mediates neurite initiation and outgrowth on laminin. Recent advances in the molecular biology of surface GalTase now allows one to increase or decrease the expression of surface GalTase, which leads to predictable consequences on lamellipodia formation, cell migration and neurite outgrowth on laminin. Finally, surface GalTase appears to function in vivo, as shown by the ability of anti-GalTase antibodies of inhibit the migration of neural crest cells in vivo. These studies define a novel molecular mechanism for cell process formation on laminin. These results lead to the next series of Specific Aims that we will pursue during the coming funding period, which are grouped into two major classes: analysis of GalTase association with the cytoskeleton and analysis of surface GalTase function during morphogenesis in vivo.