Notch信号通路与血管发育

血管发育是复杂的血管网络形成的过程,在个体发育、组织再生、肿瘤发生发展中发挥重要作用,因此具有重要的研究价值。以往研究已经证明,血管发育与细胞因子、组织缺氧、基因调控等多种因素有关。现就Notch信号通路在血管发育中的作用的研究进展作一综述。1Notch信号通路Notch信     

Notch信号通路在T淋巴细胞发育和功能中的作用

T淋巴细胞的发育是由严格的遗传程序调控的精细过程,而Notch信号通路是这一高度复杂遗传程序中最为关键的一环.Notch还与T细胞的激活和功能密切相关.此外,大量的临床和实验室研究证实,Notch信号途径的关键分子是多种人类遗传病的致病基因.Notch1受体基因的染色体易位或点突变是大多数成人T淋巴母细胞白血病的原因.该文将结合此研究室的工作,综述这一领域的相关进展.     

Notch信号通路研究进展

1917年,Morgan及其同事在果蝇体内发现一种基因,因其功能部分缺失可导致果蝇翅缘出现缺口,故命名该基因为Notch。随后的研究发现,Notch从无脊椎动物到脊椎动物的多个物种中表达,其家族成员的结构具有高度保守性,在细胞分化、发育中起着关键作用。迄今研究己阐明Notch信号通路的主要成员及核心转导过程,然而随着研究的深入,人们逐渐认识到该通路实际上处于十分复杂的调控网络之中,而这与其在发育过程中功能的多样性相符合。本文结合最新进展,系统阐述Notch信号通路的组成,功能,作用机制及调控,并揭示该通路异常与疾病的联系。     

Notch信号通路与外周免疫

Notch信号通路是一个古老的信号传导途径，在无脊椎动物和脊椎动物中广泛存在且高度保守。Notch基因在被发现后很长的一段时间内并未引起人们的注意。直到近几年，人们发现Notch信号在细胞分化和个体发育中起决定性的作用，而成为发育学、细胞生物学、免疫学、肿瘤学等多个领域的研究热点。Notch信号在免疫系统中的早期研究集中在造血系统和胸腺内淋巴细胞的发生、分化与成熟过程。而最新研究发现，Notch信号在外周成熟淋巴细胞的分化增殖过程中同样发挥着重要作用。     

Notch信号通路的研究现状

Notch信号通路是一条进化上十分保守的信号转导系统。Notch受体通过与配体的相互作用转导细胞信号,从而在细胞增殖、分化、凋亡中发挥重要的调控作用。Notch信号通路平衡细胞增殖、分化、凋亡的重要性提示其可能与肿瘤细胞的异常调控相关。近来研究发现,在许多肿瘤细胞系中存在notch基因的异常活化,且失控的Notch信号与肿瘤细胞的生长调控相关。文章综述了就新近有关Notch信号通路的生理功能及其对肿瘤细胞的调控作用。     

Notch信号通路与肝癌的研究进展

Notch信号通路是一种高度保守的信号通路,在调节细胞分化、增殖和凋亡等一系列生理病理过程中都起着关键性的作用。Notch信号在肝癌中频繁发生异常表达及激活突变,其通过多种机制促进肝癌的发生发展,且与肝癌的侵袭、转移和预后密切相关。因此,Notch信号可作为肝癌治疗的一个靶标,为肝癌的治疗提供新的方向和机遇。     

Notch信号通路与乳腺癌发生关系的研究进展

1983年Artavanis Tsakonas研究组首次克隆了Notch基因,并发现其编码一类大的跨膜受体,即Notch受体.随后相继在线虫、爪蟾、鼠和人等多个物种体内发现其家族不同成员~([1]).Notch信号不仅影响细胞的增殖、分化、凋亡、黏附和上皮细胞-间叶细胞转变(epithelial-mesenchy maltransition,EMT)等活动,在胚胎发育、造血、血细胞发育、血管生成、某些神经系统疾病及肿瘤形成等生理病理过程中起着重要的作用~([1]).     

Notch信号通路与T淋巴细胞发育

Notch信号通路在器官、细胞发育及肿瘤发生等病理生理过程中起重要作用。近年研究表明，Notch信号通路尤其是Noteh1对T淋巴细胞发育的各个阶段均有作用。Notch1能促进进入胸腺的淋巴样前体细胞向T淋巴细胞分化，抑制其向B淋巴细胞分化，并使T淋巴细胞表达TCRαβ，促进前T细胞向αβT细胞发育。此外，Notch1信号的活化可促进CD4^ CD8^ 双阳性胸腺细胞向CD8^ 单阳性细胞分化。本文综述了Notch信号通路的组成、活化，及其在T淋巴细胞发育中的作用。     

Notch信号通路与T淋巴细胞发育

Notch信号通路在器官、细胞发育及肿瘤发生等病理生理过程中起重要作用。近年研究表明 ,Notch信号通路尤其是Notch1对T淋巴细胞发育的各个阶段均有作用。Notch1能促进进入胸腺的淋巴样前体细胞向T淋巴细胞分化 ,抑制其向B淋巴细胞分化 ,并使T淋巴细胞表达TCRαβ ,促进前T细胞向αβT细胞发育。此外 ,Notch1信号的活化可促进CD4 + CD8+ 双阳性胸腺细胞向CD8+ 单阳性细胞分化。本文综述了Notch信号通路的组成、活化 ,及其在T淋巴细胞发育中的作用。     

Notch信号通路促进小鼠胸骨软骨细胞终末期成熟分化的实验研究

目的研究Notch信号通路对小鼠胸骨软骨细胞终末期成熟分化的促进作用及其成软骨分化的抑制作用。方法用鼠龄4 d昆明新生小鼠,分离和培养新生小鼠胸骨软骨细胞;NICD1慢病毒转染,提高细胞内Notch信号通路活性。实时聚合酶链反应(RT-PCR)方法检测细胞内终末期成熟分化因子和成软骨因子基因的表达;用碱性磷酸酶(ALP)染色和Alcian蓝染色方法检测软骨细胞内ALP和蛋白多糖的分泌。将细胞分为2组:对照组和NICD1组,比较两组细胞内各因子基因和蛋白的表达不同。结果新生小鼠的胸骨软骨细胞具有自发性终末期成熟分化的特点;经NICD1慢病毒转染后,软骨细胞内NICD1的蛋白表达显著提高。与对照组相比,NICD1组细胞内终末期成熟分化因子的基因表达和ALP分泌明显增加(P0.05);而成软骨分化因子的基因表达和蛋白多糖分泌明显降低(P0.05)。结论 Notch信号通路可促进小鼠胸骨软骨细胞终末期成熟分化,并抑制其向成软骨分化。     

Notch signaling in lymphocyte development

Cytokine and antigen receptor signals play well-characterized roles in promoting the survival and maturation of T and B lymphocyte progenitors through sequential developmental stages. Emerging studies suggest equally important roles for more ancient signaling pathways that evolved prior to the adaptive immune system in jawed vertebrates. In particular, there are at least two essential functions for the highly conserved Notch signaling pathway in lymphocyte development. First, Notch signals are essential for the development of T cell progenitors in the thymus and intestinal epithelium. Second, Notch signals are required to suppress B cell development in the thymus. This review will focus on focus on recent advances in our understanding of how Notch signaling regulates this developmental switch, as well as how Notch might regulate subsequent survival and cell fate decisions in developing T cells.     

Regulation of Notch signaling during T- and B-cell development by O-fucose glycans

Summary:  Notch signaling is required for the development of all T cells and marginal zone (MZ) B cells. Specific roles in T- and B-cell differentiation have been identified for different Notch receptors, the canonical Delta-like (Dll) and Jagged (Jag) Notch ligands, and downstream effectors of Notch signaling. Notch receptors and ligands are post-translationally modified by the addition of glycans to extracellular domain epidermal growth factor-like (EGF) repeats. The O -fucose glycans of Notch cell-autonomously modulate Notch–ligand interactions and the strength of Notch signaling. These glycans are initiated by protein O -fucosyltransferase 1 (Pofut1), and elongated by the transfer of N -acetylglucosamine (GlcNAc) to the fucose by β1,3GlcNAc-transferases termed lunatic, manic, or radical fringe. This review discusses T- and B-cell development from progenitors deficient in O -fucose glycans. The combined data show that Lfng and Mfng regulate T-cell development by enhancing the interactions of Notch1 in T-cell progenitors with Dll4 on thymic epithelial cells. In the spleen, Lfng and Mfng cooperate to modify Notch2 in MZ B progenitors, enhancing their interaction with Dll1 on endothelial cells and regulating MZ B-cell production. Removal of O -fucose affects Notch signaling in myelopoiesis and lymphopoiesis, and the O -fucose glycan in the Notch1 ligand-binding domain is required for optimal T-cell development.     

Notch signaling is necessary for GATA3 function in the initiation of T cell development

GATA3 and Notch1 are essential for T cell development at the earliest stage, but their mutual roles in this process remain to be clarified. In this study, we demonstrated that impairment of T lymphopoiesis in hematopoietic progenitor cells (HPC) of GATA3-deficient fetal liver (FL) on day 11.5 of gestation (E11.5) was rescued only by introduction of both GATA3 and the intracellular region of Notch1 but not by either alone. However, the introduction of GATA3 only was sufficient for T cell induction in GATA3-deficient FL cells at the advanced stage, where Notch signaling is well detectable. This indicates that Notch signaling is necessary for GATA3 to function for T cell fate specification but is not sufficient without GATA3. On the other hand, Notch signaling is sufficient for blockage of B cell development without GATA3, suggesting that T cell fate specification at the branching point does not result simply from the developmental arrest of B cell lineage by Notch signaling.     

Notch/JNK信号在低氧致大鼠皮层神经元损伤中的作用研究

目的:探讨Notch1/JNK信号通路在缺氧引起的神经元损伤中的作用。方法:原代培养新生SD大鼠皮层神经元,利用低氧条件培养建立缺氧模型。利用CCK-8实验检测在低氧诱导的不同时间,神经元的活性及siRNA干扰后神经元的活性;利用RT-q PCR与Western Blot检测对照组与低氧组神经元中NICD,p-JNK,Caspase-3mRNA与蛋白的表达情况;利用siRNA转染技术转染Notch1 siRNA或JNK siRNA至神经元中后,利用Western Blot检测低氧组与转染组神经元中NICD,p-JNK,Caspase-3蛋白的表达情况。结果:缺氧情况下神经元活性较低,具有时间依赖性;缺氧情况下,神经元的NICD,p-JNK,Caspase-3 mRNA及蛋白的表达均显著升高。抑制神经元中Notch1的活性,可进一步抑制JNK,Caspase-3的表达,改善神经元活性。结论:缺氧导致神经元Notch1信号被激活,Notch信号调节JNK的磷酸化,磷酸化的JNK进一步促进Caspase-3的激活,从而降低神经细胞的活性或促进神经细胞的死亡。     

Wnt与Notch信号通路的串话与肿瘤发生、发展的关系

肿瘤是危害人类健康与生命的常见疾病之一,其发病机制至今尚未完全探明.Wnt与Notch信号通路在生物体的生长发育中起着重要的调控作用,同时也都被证实与肿瘤相关.两条通路之间存在着许多直接或间接的串话.在肿瘤的发生发展中,二者间的相互作用取决于不同的组织背景,既可以表现为相互协同,也可以表现为相互拮抗.Wnt与Notch信号通路的串话与肿瘤的关系,在基础与临床肿瘤研究中都具有重大意义.本文对两条信号通路的组成、作用机制、相互作用,以及其串话与肺癌、皮肤癌、乳腺癌、白血病、黑色素瘤等肿瘤疾病间的关系进行了阐述与分析.     

Notch信号通路对胶质瘤干细胞的调控作用研究进展

胶质瘤干细胞(GSCs)是胶质瘤放化疗耐受和复发的重要原因.而Notch信号通路对GSCs形成、维持及胶质瘤患者放化疗耐受中起关键的调控作用.因此,深入研究GSCs中Notch信号通路调控机制对开发以该通路为靶向的治疗药物具有积极意义.     

Notch pathway regulation of neural crest cell development in vivo

Background : The function of Notch signaling in murine neural crest–derived cell lineages in vivo was examined. Results : Conditional gain (Wnt1Cre;Rosa^Notch) or loss (Wnt1Cre;RBP‐J^f/f) of Notch signaling in neural crest cells (NCCs) in vivo results in craniofacial, cardiac, and trunk abnormalities. Severe craniofacial malformations are apparent in Wnt1Cre;Rosa^Notch embryos, while less severe skull abnormalities are evident in Wnt1Cre;RBP‐J^f/f mice. Deficient cardiac neural crest migration, resulting in cardiac outflow tract malformations, occurs with increased or decreased Notch signaling in NCCs. Smooth muscle cell differentiation also is impaired in pharyngeal NCC derivatives in both Wnt1Cre;Rosa^Notch and Wnt1Cre;RBP‐J^f/f embryos. Neurogenesis is absent and gliogenesis is increased in the dorsal root ganglia of Wnt1Cre;Rosa^Notch embryos, while neurogenesis is increased and gliogenesis is decreased in Wnt1Cre;RBP‐J^f/f embryos. Conclusions : Together, these studies demonstrate essential cell‐autonomous roles for appropriate levels of Notch signaling during NCC migration, proliferation, and differentiation with critical implications in craniofacial, cardiac, and neurogenic development and disease. Developmental Dynamics 241:376–389, 2012. © 2011 Wiley Periodicals, Inc.