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1.
The adult Drosophila midgut contains multipotent intestinal stem cells (ISCs) scattered along its basement membrane that have been shown by lineage analysis to generate both enterocytes and enteroendocrine cells. ISCs containing high levels of cytoplasmic Delta-rich vesicles activate the canonical Notch pathway and down-regulate Delta within their daughters, a process that programs these daughters to become enterocytes. ISCs that express little vesiculate Delta, or are genetically impaired in Notch signaling, specify their daughters to become enteroendocrine cells. Thus, ISCs control daughter cell fate by modulating Notch signaling over time. Our studies suggest that ISCs actively coordinate cell production with local tissue requirements by this mechanism. 相似文献
2.
Xotch, the Xenopus homolog of Drosophila notch 总被引：16，自引：0，他引：16
During the development of a vertebrate embryo, cell fate is determined by inductive signals passing between neighboring tissues. Such determinative interactions have been difficult to characterize fully without knowledge of the molecular mechanisms involved. Mutations of Drosophila and the nematode Caenorhabditis elegans have been isolated that define a family of related gene products involved in similar types of cellular inductions. One of these genes, the Notch gene from Drosophila, is involved with cell fate choices in the neurogenic region of the blastoderm, in the developing nervous system, and in the eye-antennal imaginal disc. Complementary DNA clones were isolated from Xenopus embryos with Notch DNA in order to investigate whether cell-cell interactions in vertebrate embryos also depend on Notch-like molecules. This approach identified a Xenopus molecule, Xotch, which is remarkably similar to Drosophila Notch in both structure and developmental expression. 相似文献
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4.
A blood cell type termed crystal cell in Drosophila functions in clotting and wound healing and requires Notch for specification and maintenance. We report that crystal cells express elevated levels of Sima protein orthologous to mammalian hypoxia-inducible factor-α (Hif-α) even under conditions of normal oxygen availability. In these platelet-like crystal cells, Sima activates full-length Notch receptor signaling via a noncanonical, ligand-independent mechanism that promotes hemocyte survival during both normal hematopoietic development and hypoxic stress. This interaction initiates in early endosomes, is independent of Hif-β (Τangο in Drosophila), and does not activate hypoxia response targets. Studies in vertebrate myeloid cells have shown a similar up-regulation of Hif-α protein in well-oxygenated environments. This study provides a mechanistic paradigm for Hif-α/Notch interaction that may be conserved in mammals. 相似文献
5.
Differentiation-linked leukemogenesis in lymphocytes 总被引：28，自引：0，他引：28
M F Greaves 《Science (New York, N.Y.)》1986,234(4777):697-704
Most human lymphoid malignancies preserve a pattern of gene expression reflecting their proliferative activity and the development level of clonal expansion and maturation arrest. Characteristics of leukemia and other cancer cells frequently considered to reflect aberrant differentiation may more often reflect clonal selection of cell types that are normally infrequent and transitory. The differentiation status of progenitor or mature lymphoid cells influences which genetic elements are at risk of being exploited, via mutation, recombination, or deletion, for clonal advantage. These alterations may frequently arise spontaneously as a consequence of the unique developmental and functional programs of lymphoid cells and have as a major phenotypic consequence the stabilization of transitory cellular phenotypes. 相似文献
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Glial cell diversification in the rat optic nerve 总被引：43，自引：0，他引：43
M C Raff 《Science (New York, N.Y.)》1989,243(4897):1450-1455
A central challenge in developmental neurobiology is to understand how an apparently homogeneous population of neuroepithelial cells in the early mammalian embryo gives rise to the great diversity of nerve cells (neurons) and supporting cells (glial cells) in the mature central nervous system. Because the optic nerve is one of the several types of glial cells but no intrinsic neurons, it is an attractive place to investigate how neuroepithelial cells diversify. Studies of developing rat optic nerve cells in culture suggest that both cell-cell interactions and intrinsic cellular programs play important parts in glial cell diversification. 相似文献
8.
Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous 总被引：15，自引：0，他引：15
In the development of multicellular organisms a diversity of cell types differentiate at specific positions. Spacing patterns, in which an array of two or more cell types forms from a uniform field of cells, are a common feature of development. Identical precursor cells may adopt different fates because of competition and inhibition between them. Such a pattern in the developing Drosophila eye is the evenly spaced array of R8 cells, around which other cell types are subsequently recruited. Genetic studies suggest that the scabrous mutation disrupts a signal produced by R8 cells that inhibits other cells from also becoming R8 cells. The scabrous locus was cloned, and it appears to encode a secreted protein partly related to the beta and gamma chains of fibrinogen. It is proposed that the sca locus encodes a lateral inhibitor of R8 differentiation. The roles of the Drosophila EGF-receptor homologue (DER) and Notch genes in this process were also investigated. 相似文献
9.
A hallmark of aging is diminished regenerative potential of tissues, but the mechanism of this decline is unknown. Analysis of injured muscle revealed that, with age, resident precursor cells (satellite cells) had a markedly impaired propensity to proliferate and to produce myoblasts necessary for muscle regeneration. This was due to insufficient up-regulation of the Notch ligand Delta and, thus, diminished activation of Notch in aged, regenerating muscle. Inhibition of Notch impaired regeneration of young muscle, whereas forced activation of Notch restored regenerative potential to old muscle. Thus, Notch signaling is a key determinant of muscle regenerative potential that declines with age. 相似文献
10.
Specific expression of nuclear proto-oncogenes before entry into meiotic prophase of spermatogenesis 总被引：15，自引：0，他引：15
The expression of proto-oncogenes representative of several functional categories has been investigated during development of mouse male germ cells. The c-raf proto-oncogene and three members of the c-ras gene family were expressed in mitotically active stem cells, throughout the prophase of meiosis and to varying extents in post-meiotic cell types. In contrast, the nuclear proto-oncogenes c-fos, c-jun, and c-myc were specifically expressed at high levels in type B spermatogonia. High levels of c-myc and c-jun RNAs were also detected in spermatocytes early in the prophase of meiosis. The type B spermatogonia represent the last mitotic cell division before entry into meiotic prophase; therefore, these nuclear proto-oncogenes may be involved in altering programs of gene expression at this developmental transition. 相似文献
11.
Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells 总被引：1，自引：0，他引：1
Shen Q Goderie SK Jin L Karanth N Sun Y Abramova N Vincent P Pumiglia K Temple S 《Science (New York, N.Y.)》2004,304(5675):1338-1340
Neural stem cells are reported to lie in a vascular niche, but there is no direct evidence for a functional relationship between the stem cells and blood vessel component cells. We show that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulates neuroepithelial cell contact, activating Notch and Hes 1 to promote self-renewal. These findings identify endothelial cells as a critical component of the neural stem cell niche. 相似文献
12.
The "segmentation clock" is thought to coordinate sequential segmentation of the body axis in vertebrate embryos. This clock comprises a multicellular genetic network of synchronized oscillators, coupled by intercellular Delta-Notch signaling. How this synchrony is established and how its loss determines the position of segmentation defects in Delta and Notch mutants are unknown. We analyzed the clock's synchrony dynamics by varying strength and timing of Notch coupling in zebra-fish embryos with techniques for quantitative perturbation of gene function. We developed a physical theory based on coupled phase oscillators explaining the observed onset and rescue of segmentation defects, the clock's robustness against developmental noise, and a critical point beyond which synchrony decays. We conclude that synchrony among these genetic oscillators can be established by simultaneous initiation and self-organization and that the segmentation defect position is determined by the difference between coupling strength and noise. 相似文献
13.
目的 研究Notch1在肝癌组织及细胞中的表达并初步探讨Notch1下调后诱导肝癌细胞调亡的机制。方法 2016年3月至2016年9月于广东医科大学附属医院肝胆外科收集32例肝癌病人样本,利用qRT-PCR方法检测肝癌癌组织及癌旁组织中Notch1基因的表达,免疫组化检测组织中Notch1蛋白表达,siRNA沉默肝癌细胞Notch1表达,流式细胞术检测细胞凋亡情况,Western blot方法检测Notch1、Bcl2和Bax蛋白表达,统计分析Notch1表达水平与肝癌病人临床诊断指标甲胎蛋白（AFP）的相关性。结果 肝癌组织标本中Notch1高表达率为71.9%（23/32）,明显高于癌旁组织的28.1%（9/32）,差异具有显著统计学意义（P<0.01）;Pearson相关性分析显示,Notch1与AFP存在正相关性（R2=0.3376,P=0.0036）;免疫组化验证Notch1蛋白分别在肝癌癌组织样本中高表达和癌旁组织中低表达;siRNA干扰Notch1基因表达后,镜下发现肝癌细胞4401增殖抑制,流式检测示转染组明显凋亡,蛋白免疫印迹显示凋亡相关蛋白Bcl2蛋白下调、Bax表达上调。结论 Notch1与肝癌的发生、发展相关,下调Notch1可诱导肝癌细胞凋亡,同时Notch1还可作为临床治疗肝癌的潜在新靶点。 相似文献
14.
Notch proteins are receptors for a conserved signaling pathway that affects numerous cell fate decisions. We found that in Drosophila, Protein O-fucosyltransferase 1 (OFUT1), an enzyme that glycosylates epidermal growth factor-like domains of Notch, also has a distinct Notch chaperone activity. OFUT1 is an endoplasmic reticulum protein, and its localization was essential for function in vivo. OFUT1 could bind to Notch, was required for the trafficking of wild-type Notch out of the endoplasmic reticulum, and could partially rescue defects in secretion and ligand binding associated with Notch point mutations. This ability of OFUT1 to facilitate folding of Notch did not require its fucosyltransferase activity. Thus, a glycosyltransferase can bind its substrate in the endoplasmic reticulum to facilitate normal folding. 相似文献
15.
Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop 总被引：1，自引：0，他引：1
Hirata H Yoshiura S Ohtsuka T Bessho Y Harada T Yoshikawa K Kageyama R 《Science (New York, N.Y.)》2002,298(5594):840-843
16.
Epigenetic reprogramming in mammalian development 总被引：1，自引：0，他引：1
DNA methylation is a major epigenetic modification of the genome that regulates crucial aspects of its function. Genomic methylation patterns in somatic differentiated cells are generally stable and heritable. However, in mammals there are at least two developmental periods-in germ cells and in preimplantation embryos-in which methylation patterns are reprogrammed genome wide, generating cells with a broad developmental potential. Epigenetic reprogramming in germ cells is critical for imprinting; reprogramming in early embryos also affects imprinting. Reprogramming is likely to have a crucial role in establishing nuclear totipotency in normal development and in cloned animals, and in the erasure of acquired epigenetic information. A role of reprogramming in stem cell differentiation is also envisaged. DNA methylation is one of the best-studied epigenetic modifications of DNA in all unicellular and multicellular organisms. In mammals and other vertebrates, methylation occurs predominantly at the symmetrical dinucleotide CpG (1-4). Symmetrical methylation and the discovery of a DNA methyltransferase that prefers a hemimethylated substrate, Dnmt1 (4), suggested a mechanism by which specific patterns of methylation in the genome could be maintained. Patterns imposed on the genome at defined developmental time points in precursor cells could be maintained by Dnmt1, and would lead to predetermined programs of gene expression during development in descendants of the precursor cells (5, 6). This provided a means to explain how patterns of differentiation could be maintained by populations of cells. In addition, specific demethylation events in differentiated tissues could then lead to further changes in gene expression as needed. Neat and convincing as this model is, it is still largely unsubstantiated. While effects of methylation on expression of specific genes, particularly imprinted ones (7) and some retrotransposons (8), have been demonstrated in vivo, it is still unclear whether or not methylation is involved in the control of gene expression during normal development (9-13). Although enzymes have been identified that can methylate DNA de novo (Dnmt3a and Dnmt3b) (14), it is unknown how specific patterns of methylation are established in the genome. Mechanisms for active demethylation have been suggested, but no enzymes have been identified that carry out this function in vivo (15-17). Genomewide alterations in methylation-brought about, for example, by knockouts of the methylase genes-result in embryo lethality or developmental defects, but the basis for abnormal development still remains to be discovered (7, 14). What is clear, however, is that in mammals there are developmental periods of genomewide reprogramming of methylation patterns in vivo. Typically, a substantial part of the genome is demethylated, and after some time remethylated, in a cell- or tissue-specific pattern. The developmental dynamics of these reprogramming events, as well as some of the enzymatic mechanisms involved and the biological purposes, are beginning to be understood. Here we look at what is known about reprogramming in mammals and discuss how it might relate to developmental potency and imprinting. 相似文献
17.
C A Ettensohn 《Science (New York, N.Y.)》1990,248(4959):1115-1118
In many organisms, interactions between cells play a critical role in the specification of cell fates. In the sea urchin embryo, primary mesenchyme cells (PMCs) regulate the developmental program of a subpopulation of secondary mesenchyme cells (SMCs). The timing of this cell interaction was analyzed by means of a fluorescence photoablation technique, which was used to specifically ablate PMCs at various stages of development. In addition, the PMCs were microinjected into PMC-depleted recipient embryos at different developmental stages and their effect on SMC fate was examined. The critical interaction between PMCs and SMCs was brief and took place late in gastrulation. Before that time, SMCs were insensitive to the suppressive signals transmitted by the PMCs. 相似文献
18.
Cell alignment required in differentiation of Myxococcus xanthus 总被引：13，自引：0，他引：13
During fruiting body morphogenesis of Myxococcus xanthus, cell movement is required for transmission of C-factor, a short range intercellular signaling protein necessary for sporulation and developmental gene expression. Nonmotile cells fail to sporulate and to express C-factor-dependent genes, but both defects were rescued by a simple manipulation of cell position that oriented the cells in aligned, parallel groups. A similar pattern of aligned cells normally results from coordinated recruitment of wildtype cells into multicellular aggregates, which later form mature fruiting bodies. It is proposed that directed cell movement establishes critical contacts between adjacent cells, which are required for efficient intercellular C-factor transmission. 相似文献
19.
Generalized potential of adult neural stem cells 总被引：1，自引：0，他引：1
Clarke DL Johansson CB Wilbertz J Veress B Nilsson E Karlström H Lendahl U Frisén J 《Science (New York, N.Y.)》2000,288(5471):1660-1663
The differentiation potential of stem cells in tissues of the adult has been thought to be limited to cell lineages present in the organ from which they were derived, but there is evidence that some stem cells may have a broader differentiation repertoire. We show here that neural stem cells from the adult mouse brain can contribute to the formation of chimeric chick and mouse embryos and give rise to cells of all germ layers. This demonstrates that an adult neural stem cell has a very broad developmental capacity and may potentially be used to generate a variety of cell types for transplantation in different diseases. 相似文献
20.
Notch信号通路是一条进化上十分保守的信号转导系统,在调节干细胞增殖、分化和凋亡方面起到重要作用。研究表明,鹿生茸区骨膜和角柄骨膜分别含有鹿茸发生和再生的干细胞。应用RT-PCR的方法对离体培养生茸区骨膜和角柄骨膜细胞进行检测,得出Notch信号通路各信号因子在2种细胞中的表达情况。结果:Notch-1、Notch-2、Notch-4、Dll-4J、agged-1J、agged-2、Hes-1等信号因子在这2种干细胞中均有不同程度的表达,说明Notch信号通路可能参与了他们的增殖、分化的调控。 相似文献