Notch信号通路对干细胞分化的影响

干细胞的增殖分化受到自身或外在、远程或近程多种信号通路的调控,而细胞之间的相互通讯在此过程中起到重要作用。Notch通路就是通过相邻细胞之间相互通讯调控细胞分化的重要信号通路之一,众多研究显示,该通路的活化在干细胞分化过程中发挥了重要调节作用,本文就此相关研究进展作一简要综述。     

Wt1在心脏发育中的作用

Wt1最初被认为是一种抑癌基因,现在发现其在器官形成和病理生理过程中发挥作用,它不仅影响肾脏而且影响心脏的发育。心外膜细胞在经历了上皮-间充质细胞转化后成为心血管前体细胞,之后继续分化为心肌细胞、冠状动脉血管细胞等,该过程在心脏发育中起到重要作用,而Wt1调控了这一重要的转化过程。本综述主要阐述Wt1通过Wnt/β-catenin信号通路和维甲酸信号通路调控EMT,影响心脏发育的机制。充分理解Wt1调控EMT产生心血管前体细胞的过程与分子机制,对于研究正常心脏发育及心脏再生有很大帮助。     

眼睛发育与骨形成蛋白信号通路的关系

在早期胚胎发育过程中,眼睛是由起源于不同胚层的几个部分经过一系列的诱导作用以及时间和空间上的相互协调作用形成的复杂而又具有精确功能的器官。在眼睛的形成发育过程中,许多信号通路及其相关的调控因子发挥着重要作用。本文主要关注眼睛发育过程与骨形成蛋白(BMP)信号通路的关系,BMP信号的激活能够诱导晶状体的再生和CLT(角膜到晶状体的分化转移)进程,维持睫状体的功能,促进视网膜的发生,影响巩膜的重塑和泪腺的发育。很多眼部疾病的发生与BMP信号通路的调节紊乱密切相关,因此可以将BMP信号通路作为一个潜在的药物靶点来探究治疗眼部疾病的方法。本文就BMP信号通路对眼睛发育的影响作一综述。     

FGF信号通路在内耳发育调控和毛细胞再生中的作用

内耳是感受听觉和平衡觉的复杂器官。在内耳发育过程中,成纤维生长因子(fibroblast growth factor, FGF)信号通路参与了听基板的诱导、螺旋神经节(statoacoustic ganglion, SAG)的发育以及Corti器感觉上皮的分化。FGF信号开启了内耳早期发育的基因调控网络,诱导前基板区域以及听基板的形成。正常表达的FGF信号分子可促进听囊腹侧成神经细胞的特化,但成熟SAG神经元释放的过量FGF5可抑制此过程,形成负反馈环路使SAG在稳定状态下发育。FGF20在Notch信号通路的调控下参与了前感觉上皮区域向毛细胞和支持细胞的分化过程,而内毛细胞分泌的FGF8可调控局部支持细胞分化为柱细胞。人类FGF信号通路异常可导致多种耳聋相关遗传病。此外,FGF信号通路在低等脊椎动物毛细胞自发再生以及干细胞向内耳毛细胞诱导过程中都起到了关键作用。本文综述了FGF信号通路在内耳发育调控以及毛细胞再生中的作用及其相关研究进展,以期为毛细胞再生中FGF信号通路调控机制的阐明奠定理论基础。     

经典WNT信号通路与哺乳动物肺器官发育

肺器官发育是上皮和问充质相互作用的过程,由多条信号通路共同调控。已知经典WNT信号通路对细胞的增殖、凋亡和分化起着重要的调控作用,在小鼠等模式生物上研究发现,它也参与了哺乳动物肺器官发育的调控过程。综述近年来经典WNT信号通路成员在哺乳动物肺器官发育过程中的表达变化、作用功能及表达异常可能诱发的肺部疾病,以期为研究经典WNT信号通路调控人类肺器官发育的分子机制及相关肺部疾病的诊治奠定基础。     

p62蛋白功能及相关信号通路研究

p62是一种多功能蛋白,其蛋白分子包含多个结构域,通过与不同蛋白质结合形成细胞中重要的信号中心,从而调控多种信号通路,影响细胞的生长、衰老,甚至死亡等生理过程。p62蛋白通过对mTORC1信号通路的影响在氨基酸信号通路中发挥着关键的调控作用。p62蛋白是自噬体与底物之间的适配蛋白,在细胞自噬过程中起到分子调节器的作用。p62蛋白具有质核穿梭功能,在DNA损伤修复和氧化应激反应中具有重要作用,其异常积累会引起细胞的恶性转变,导致肿瘤的发生。现综述p62在调节多种信号通路,如自噬、氨基酸感知、凋亡及肿瘤发生等过程中的作用。     

参与真菌形态及毒力形成的信号转导通路的研究进展

自然界中,无论单细胞还是多细胞生物,都是通过信号通路与周围环境相互作用来维持自身的稳态和生理状态,真菌也是利用其信号系统来感应外界环境的变化并调控繁殖、发展和毒力,信号转导系统是一个多因素共同参与的极其复杂的过程。真菌通过其信号传导系统(主要有双组份信号传导系统、MAPK信号系统、c AMP-PKA信号系统)感受并将变化了的环境信号因子级联传递至细胞内,引起特定的基因表达,参与调控细胞生长、发育、分裂和分化等诸多生理及病理过程,并在基因表达调控和细胞质功能活动中发挥作用。对这些传导通路的了解不仅有助于阐明各通路在病原真菌毒力调控过程中的作用机制,而且还为寻找新的抗真菌药物的作用靶点提供帮助。该文将综述真菌中几种重要信号转导通路的研究进展。     

Hippo信号通路调控天然免疫的研究进展

Hippo信号通路在细胞的增殖、分化以及凋亡等方面扮演着重要的角色.同时Hippo信号通路又是响应多种环境条件的效应器,如葡萄糖饥饿、细胞密度、病原体感染以及热激等.近年来的研究发现, Hippo信号通路在天然免疫中具有重要的作用.更为重要的是, Hippo信号通路在调控天然免疫过程中,存在核心蛋白相互不依赖的特征, YAP(yes-associated protein)对天然免疫的调节往往独立于上游激酶的调控.同时,在不同的组织和物种中YAP的抵抗病原体的作用也存在差异.本文从Hippo信号通路的演化、调控关系以及Hippo信号通路在抗病毒和抗细菌中的作用,阐述了Hippo信号通路与天然免疫的关系.     

小G蛋白RhoA与细胞发育

细胞发育是细胞内各种复杂反应在时间和空间上有序协调的过程, 包括细胞增殖、胞质分裂、细胞运动、细胞分化和组织生成等．作为G蛋白家族重要成员的RhoA起了重要的调控作用：在G蛋白调控因子(如GEF XPLN、 p115RhoGEF、p190RhoGAP等）的作用下,活化的RhoA依次与效应蛋白分子（如ROCK1/2、 mDia、 PRK1/2、 citron 激酶等）结合, 从而开启了下游的信号通路, 最终使细胞能够迅速地对外界刺激做出反应．干细胞是一类既能自我更新又能特异分化形成终末分化细胞的细胞, 而 RhoA对干细胞的自我更新和定向分化也起着“开关"作用, 对RhoA信号通路的调节调控了胚胎发生、神经发生、造血生成及成骨和肌肉生成等干细胞分化发育过程．肿瘤是正常细胞在各种因素长期作用下增殖异常的产物, 而RhoA异常表达与肿瘤的发生、侵润与转移密切相关, RhoA信号通路与p53等基因的交互作用在肿瘤的发育过程中也发挥了重要的作用．     

Rho蛋白和细胞骨架的关系

Rho蛋白作为细胞信号转导的分子开关之一,在细胞骨架动态变化中发挥着极其重要的作用。Rho蛋白对细胞骨架动态变化的调节是一个复杂的信号传递过程,涉及到Rho蛋白介导的信号通路中不同效应物间和Rho蛋白介导的多条信号通路间的相互作用。在Rho蛋白介导的信号通路中,上游调控因子、Rho蛋白、效应物在细胞中的正确定位对信号传递有着决定性的作用。     

Evolving complexity of MIF signaling

Macrophage migration inhibitory factor (MIF) is a cytokine expressed in various cell types, including hematopoietic, epithelial, endothelial, mesenchymal and neuronal cells. Altered MIF expression has been associated with a multitude of diseases ranging from inflammatory disorders like sepsis, lupus and rheumatoid arthritis to organ pathologies such as heart failure, myocardial infarction, acute kidney injury, organ fibrosis and a number of malignancies. The implication of MIF in these diseases was supported by numerous animal studies. MIF acts in an autocrine and paracrine manner via binding and activating the receptors CD74/CD44, CXCR2, CXCR4 and CXCR7. Upon receptor binding, several downstream signaling pathways were shown to be activated in vivo, including ERK1/2, AMPK and AKT. Expression of MIF receptors is not uniform in various cells, resulting in differential responses to MIF across various tissues and pathologies. Within cells, MIF can directly bind and interact with intracellular proteins, such as the constitutive photomorphogenic-9 (COP9) signalosome subunit 5 (CSN5), p53 or thioredoxin-interacting protein (TXNIP). D-dopachrome tautomerase (D-DT or MIF-2) was recognized to be a structural and functional homolog of MIF, which could exert overlapping effects, raising further the complexity of canonical MIF signaling pathways. Here, we provide an overview of the expression and regulation of MIF, D-DT and their receptors. We also discuss the downstream signaling pathways regulated by MIF/D-DT and their pathological roles in different tissue, particularly in the heart and the kidney.     

EndMT: A promising and controversial field

The endothelial to mesenchymal transition (EndMT) is the process by which endothelial cells lose a portion of their cellular features and obtain certain characteristics of mesenchymal cells, including loss of tight junctions, increased motility, and increased secretion of extracellular matrix proteins. EndMT is involved in cardiac development and a variety of diseases processes, such as vascular or tissue fibrosis and tumor. However, its role in specific diseases remains under debate. This review summarizes EndMT-related diseases, existing controversies, different types of EndMT, and molecules and signaling pathways associated with the process.     

EPH receptors in cancer

EPH receptors and their ephrin ligands constitute the largest sub-family of receptor tyrosine kinases (RTKs) and are components of cell signaling pathways involved in animal development. The ability of the EPH/ephrin guidance system to position cells and modulate cell morphology underlies their various roles in development. In addition, EPH signaling plays an important role in oncogenic processes observed in several organs. These receptors are involved in a wide range of processes directly related with tumorigenesis and metastasis, including cell attachment and shape, migration, and angiogenesis. Accordingly, deregulation of EPH expression and signaling activity could be crucial for the tumorigenic process. This review focuses on EPH receptors' roles in oncogenic transformation and tumor progression.     

Development of the renal glomerulus: good neighbors and good fences

The glomerulus of the mammalian kidney is an intricate structure that contains an unusual filtration barrier that retains higher molecular weight proteins and blood cells in the circulation. Recent studies have changed our conception of the glomerulus from a relatively static structure to a dynamic one, whose integrity depends on signaling between the three major cell lineages: podocytes, endothelial and mesangial cells. Research into the signaling pathways that control glomerular development and then maintain glomerular integrity and function has recently identified several genes, such as the nephrin and Wilms' tumor 1 genes, that are mutated in human kidney disease.     

CD2-associated protein is widely expressed and differentially regulated during embryonic development

CD2-associated protein (CD2AP) is an adapter protein that is involved in various signaling and vesicular trafficking processes and also functions as a linker between plasma membrane proteins and the actin cytoskeleton. The protein is known to have important functions in T cells and glomerular podocytes, but it is also expressed by many other adult-type tissues and cells. Here we analyzed the expression of the protein during early embryonic development and organogenesis of the mouse. The results showed differential tissue-specific regulation of CD2AP in developing and maturing organs. In oocytes and pre-implantation embryos, CD2AP was located diffusely in the cytoplasm, whereas in late blastocysts it was concentrated to the intercellular contacts. During organogenesis, CD2AP was distinctly upregulated upon, e.g., the pretubular aggregation of metanephric mesenchyme cells and the appearance of the osteoblastic rim around cartilages during endochondral ossification. High CD2AP expression was also observed during epithelial-like conversion of some highly specialized secretory cell types such as the odontoblasts, the cells of the choroid plexus and the decidualized cells of the endometrial stroma. In other instances, such as the development of the proximal tubuli of the kidney and the flat alveolar epithelium of the lung, the protein was downregulated upon differentiation and maturation of the cells. Finally, certain cells, e.g., glomerular podocytes, those forming the collecting ducts of the kidney, and the urothelium of the kidney pelvis, expressed CD2AP throughout their differentiation and maturation. Multiple molecules and complex pathways regulate embryogenesis, and scaffolding proteins apparently have pivotal roles in targeting and finetuning, e.g., growth factor- or hormone-induced processes. The cell-type specific spatio-temporal regulation of CD2AP during development suggests that this adapter protein is a key regulatory partner in many signaling pathways and cellular processes governing differentiation and morphogenesis.