Notch和Wnt信号通路在血管形成中的协同调控作用

Notch和Wnt信号通路能够调控细胞的分化、增殖、迁移和粘附等多种行为,在胚胎发育、干细胞分化及肿瘤生长等方面发挥多样性的调控作用.血管形成过程中的典型事件包括尖端细胞(tipcell)和柄细胞(stalkcell)分化、柄细胞增殖、内皮细胞迁移和粘附、血管重塑以及动静脉分化等.本文对Notch和Wnt信号通路在血管形成不同阶段的功能作一综述,以期描述Notch和Wnt是怎样在分子水平上协同作用进而调控血管的形成.从两条信号通路的分子水平及复杂信号网络中众多成员协调作用的角度了解血管形成的机制,对于调整肿瘤等涉及血管形成的相关疾病的治疗策略具有一定意义.     

Activation of Notch1 in the hair follicle leads to cell-fate switch and Mohawk alopecia

The Notch signaling pathway has been shown to control cell-fate decisions during mouse development. To study the role of Notch1 in epidermal differentiation and the development of the various cell types within the mouse hair follicle, we generated transgenic mice that express a constitutive activated form of Notch1 under the control of the involucrin promoter. Transgenic animals express the transgene in the suprabasal epidermal keratinocytes and inner root sheath of the hair follicle, and develop both skin and hair abnormalities. Notch1 overexpression leads to an increase of the differentiated cell compartment in the epidermis, delays inner root sheath differentiation, and leads to hair shaft abnormalities and alopecia associated with the anagen phase of the hair cycle.     

Notch信号通路与卵巢生理病理

Notch是对脊椎和无脊椎动物的系统发育、肿瘤发生等生理病理过程十分重要的一类信号受体家族。活化的Notch受体与其配体结合后,通过两次水解而释放其胞内段,后者入核后与转录因子CSL家族结合而激活靶基因,精确调控各谱系细胞的分化、增殖和凋亡,在细胞命运决定中起关键作用。近来研究表明,Notch信号通路与卵巢生理病理密切相关。     

Notch 信号通路与淋巴细胞发育

Notch 信号通路为一广泛应用且高度保守的信号转导途径,决定多能祖细胞的分化方向,其中在共同淋巴祖细胞向 T 淋巴细胞或 B 淋巴细胞分化选择中具有决定性作用 . Notch 信号通路参与淋巴细胞的发育过程,促进 Tαβ细胞的形成、诱导处女型 T 细胞变为调节型 T 细胞、阻止 CD4+T 细胞向 Th1 类型分化,以及增加外周免疫器官边缘区 B 细胞的数量 . 在分析 Notch 蛋白结构的基础上,综合最新进展,系统阐明了 Notch 信号通路的组成、作用机制、参与的淋巴细胞发育过程以及所起的作用 .     

牙齿发育与FGF 信号通路的关系

牙齿发育的过程,是一个连续并且复杂的过程。牙齿发育的分子机制可总结为:通过外胚层来源的上皮和其下方的间充质相互作用,来调节牙齿的形态学发生。成纤维细胞生长因子(Fibroblast Growth Factor,FGF)是一类肽类分子,它们通过与细胞膜上特异性受体的结合来发挥作用,以此来调节细胞生长。并且具有多种生物活性,是胚胎生长发育和成体组织创伤修复中最具有重要功能的细胞因子。通过众多科学研究,牙齿发育与FGF信号通路的关系已经研究的比较透彻,在牙齿的生长发育过程中,FGF发挥了关键性作用。     

Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development

Heart development requires contributions from, and coordinated signaling interactions between, several cell populations, including splanchnic and pharyngeal mesoderm, postotic neural crest and the proepicardium. Here we report that Fgf3 and Fgf10, which are expressed dynamically in and near these cardiovascular progenitors, have redundant and dosage sensitive requirements in multiple aspects of early murine cardiovascular development. Embryos with Fgf3^−/+;Fgf10^−/−, Fgf3^−/−;Fgf10^−/+ and Fgf3^−/−;Fgf10^−/− genotypes formed an allelic series of increasing severity with respect to embryonic survival, with double mutants dead by E11.5. Morphologic analysis of embryos with three mutant alleles at E11.5–E13.5 and double mutants at E9.5–E11.0 revealed multiple cardiovascular defects affecting the outflow tract, ventricular septum, atrioventricular cushions, ventricular myocardium, dorsal mesenchymal protrusion, pulmonary arteries, epicardium and fourth pharyngeal arch artery. Assessment of molecular markers in E8.0–E10.5 double mutants revealed abnormalities in each progenitor population, and suggests that Fgf3 and Fgf10 are not required for specification of cardiovascular progenitors, but rather for their normal developmental coordination. These results imply that coding or regulatory mutations in FGF3 or FGF10 could contribute to human congenital heart defects.     

FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development

FGF10 plays an important role in the morphogenesis of several tissues by control of mesenchymal-to-epithelial signaling. In the pancreas, mesenchymal FGF10 is required to maintain the Pdx1-expressing epithelial progenitor cell population, and in the absence of FGF10 signaling, these cells fail to proliferate. Ectopic expression of FGF10 in the pancreatic epithelium caused increased proliferation of pancreatic progenitor cells and abrogation of pancreatic cell differentiation of all cell types. A hyperplastic pancreas consisting of undifferentiated cells expressing Pdx1, Nkx6.1, and cell adhesion markers normally characterizing early pancreatic progenitor cells resulted. Differentiation was attenuated even as proliferation of the pancreatic cells slowed during late gestation, suggesting that the trophic effect of FGF10 was independent of its effects upon cell differentiation. The FGF10-positive pancreatic cells expressed Notch1 and Notch2, the Notch-ligand genes Jagged1 and Jagged2, as well as the Notch target gene Hes1. This activation of Notch is distinct from the previously recognized mechanism of lateral inhibition. These data suggest that FGF10 signaling serves to integrate cell growth and terminal differentiation at the level of Notch activation, revealing a novel second role of this key signaling system during pancreatic development.     

Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment

Matrix metalloproteinases (MMPs) have long been thought of as critical factors regulating matrix degradation associated with cell invasion into ectopic tissue compartments during primary tumor growth and metastasis. One member of the MMP family historically linked to these invasive processes is MMP-9/gelatinase B. By studying a transgenic mouse model of de novo epithelial carcinogenesis, new roles for MMP-9 have emerged that broaden the view of its functional contribution to malignant progression. The combined implication of these studies suggest that MMP-9 functionally contributes to cancer development; however, its major regulatory role may be in its ability to activate poorly diffusible and/or matrix-sequestered growth factors that regulate epithelial and/or endothelial cell growth as opposed to regulating cellular invasion across basement membranes.     

诱导心脏发生的早期信号通路

心脏是胚胎发生过程中最早形成的器官 .心脏前体的特化是组织间及细胞与细胞之间相互作用的结果 ,这一过程包含了诱导信号作用的时间和空间完整程序 .以脊椎动物和无脊椎动物作为模式动物 ,总结了在早期心脏发生中发挥重要作用的诱导信号通路 :BMP Dpp ,Wnt Wingless ,FGF及Notch信号通路 ,并阐述了信号通路之间的通讯 (crosstalk)以及信号通路与心脏发生相关的关键转录调节因子之间的协同诱导作用 .     

The Notch signaling pathway in retinal dysplasia and retina vascular homeostasis

The retina is one of the most essential elements of vision pathway in vertebrate. The dysplasia of retina cause congenital blindness or vision disability in individuals, and the misbalance in adult retinal vascular homeostasis leads to neovaseularization-associated diseases in adults, such as diabetic retinopathy or age-related macular degeneration. Many developmental signaling pathways are involved in the process of retinal development and vascular homeostasis. Among them, Notch signaling pathway has long been studied, and Notch signaling-interfered mouse models show both neural retina dysplasia and vascular abnormality. In this review, we discuss the roles of Notch signaling in the maintenance of retinal progenitor cells, specification of retinal neurons and glial cells, and the sustaining of retina vascular homeostasis, especially from the aspects of conditional knockout mouse models. The potential of Notch signal mampulation may provide a powerful cell fate- and neovascularization-controlling tool that could have important applications in la'eatment of retinal diseases.     

When MT1-MMP meets ADAMs

MT1-MMP is a membrane-tethered enzyme capable of remodeling extracellular matrix. MT1-MMP-deficient mice exhibit systematic defects during development, especially in craniofacial development characterized by retarded calvarial bone formation. Recently, we identified MT1-MMP as a critical positive modulator of FGF signaling during intramembranous ossification. MT1-MMP cleaves ADAM9 to protect FGFR2 from ectodomain shedding. Depletion of ADAM9 in MT1-MMP-deficient mice significantly rescued the calvarial defects via restoring FGF signaling. Interestingly, this regulatory mechanism seems to be highly tissue-specific, as defective FGF2-induced corneal angiogenesis in Mmp14^?/? mice could not be rescued by removal of ADAM9. In addition, MT1-MMP also cleaves another ADAM family member, ADAM15. Our current findings not only present a novel regulatory mechanism for FGF signaling but also reveal a functional crosstalk between MMP and ADAM families. Better understanding of the interplay between ADAMs and MT1-MMP and its consequences for signaling pathways will provide new insights into therapeutic approaches for the management of developmental disorders and various diseases, such as cancer.