Ogata Souichi, Morokuma Junji, Hayata Tadayoshi, Kolle Gabriel, Niehrs Christof, Ueno Naoto, Cho Ken W Y
Department of Developmental and Cell Biology, Developmental Biology Center, University of California at Irvine, Irvine, California 92697, USA.
Genes Dev. 2007 Jul 15;21(14):1817-31. doi: 10.1101/gad.1541807.
The molecular mechanisms governing the cell behaviors underlying morphogenesis remain a major focus of research in both developmental biology and cancer biology. TGF-beta ligands control cell fate specification via Smad-mediated signaling. However, their ability to guide cellular morphogenesis in a variety of biological contexts is poorly understood. We report on the discovery of a novel TGF-beta signaling-mediated cellular morphogenesis occurring during vertebrate gastrulation. Activin/nodal members of the TGF-beta superfamily induce the expression of two genes regulating cell adhesion during gastrulation: Fibronectin Leucine-rich Repeat Transmembrane 3 (FLRT3), a type I transmembrane protein containing extracellular leucine-rich repeats, and the small GTPase Rnd1. FLRT3 and Rnd1 interact physically and modulate cell adhesion during embryogenesis by controlling cell surface levels of cadherin through a dynamin-dependent endocytosis pathway. Our model suggests that cell adhesion can be dynamically regulated by sequestering cadherin through internalization, and subsequent redeploying internalized cadherin to the cell surface as needed. As numerous studies have linked aberrant expression of small GTPases, adhesion molecules such as cadherins, and TGF-beta signaling to oncogenesis and metastasis, it is tempting to speculate that this FLRT3/Rnd1/cadherin pathway might also control cell behavior and morphogenesis in adult tissue homeostasis.
在发育生物学和癌症生物学领域，研究形态发生过程中细胞行为的分子机制仍然是一个主要焦点。转化生长因子-β（TGF-β）配体通过Smad介导的信号传导控制细胞命运的决定。然而，它们在多种生物学背景下引导细胞形态发生的能力却鲜为人知。我们报告了在脊椎动物原肠胚形成过程中发现的一种由TGF-β信号介导的新型细胞形态发生现象。TGF-β超家族的激活素/节点成员在原肠胚形成过程中诱导两个调节细胞黏附的基因表达：富含亮氨酸重复序列的纤连蛋白跨膜蛋白3（FLRT3），一种含有细胞外富含亮氨酸重复序列的I型跨膜蛋白，以及小GTP酶Rnd1。FLRT3和Rnd1在胚胎发育过程中通过依赖发动蛋白的内吞途径控制钙黏蛋白的细胞表面水平，从而在物理上相互作用并调节细胞黏附。我们的模型表明，细胞黏附可以通过内化隔离钙黏蛋白，并随后根据需要将内化的钙黏蛋白重新部署到细胞表面来进行动态调节。由于许多研究已将小GTP酶、钙黏蛋白等黏附分子以及TGF-β信号的异常表达与肿瘤发生和转移联系起来，因此很容易推测，这种FLRT3/Rnd1/钙黏蛋白途径也可能在成体组织稳态中控制细胞行为和形态发生。
