自引率: 2.1%
被引量: 4561
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投稿须知/期刊简介:
Mechanisms of Development is an international journal whose purpose is to communicate contemporary studies in developmental biology with special emphasis on the characterization of molecular mechanisms underlying development processes in either vertebrates, invertebrates or plants. Areas of particular interest include embryogenesis, pattern formation, cell determination and differentiation, specification of tissue type, targetted disruptions of developmental control genes, the roles of transcription factor in development, regulatory hierarchies of gene expression, cell-cell communication and signal transduction in development, as well as post-transcriptional controls of developmental processes such as regulated splicing and protein modification.Such a focus should provide a unique forum for comparing and contrasting strategies of development among a wide spectrum of organisms. The Editors are strongly committed to establishing the highest standards of quality and scientific merit, and guarantee rapid communication of important contributions.NOTE: A combined MOD subscription and ISDB membership is now available through Elsevier's Customer Service Department. The price for 1999 has been fixed at 125.00 US Dollars (plus VAT for residents of the European Union). Further information: please contact the nearest Regional Sales Office
期刊描述简介:
Mechanisms of Development is an international journal that communicates current studies in developmental biology in any model system like animals and plants, these may focus on molecular and/or cellular mechanisms. MOD is the official journal of The International Society of Developmental Biologists which supports the world-wide community of developmental biologists. Areas of particular interest include: Cell and tissue morphogenesis including migration, shape and polarity, and the roles of physical forces in development Developmental cell biology Regulation of stem cell and progenitor maintenance and cell differentiation Evolution of developmental mechanisms Pre and/or post-embryonic development of tissues and organs Manuscripts involving in vitro approaches to study mechanisms relevant to developmental biology; e.g., cell culture assays to study stem cell properties or basic cell biological mechanisms are also accepted and we also welcome studies using modelling approaches that are firmly rooted in experimental data. Mechanisms of Development does not publish descriptive studies of gene expression patterns and molecular screens; for submission of such studies see Gene Expression Patterns
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CFTR deficiency causes cardiac dysplasia during zebrafish embryogenesis and is associated with dilated cardiomyopathy.
Mutations in the CFTR gene cause cystic fibrosis (CF) with myocardial dysfunction. However, it remains unknown whether CF-related heart disease is a secondary effect of pulmonary disease, or an intrinsic primary defect in the heart. Here, we used zebrafish, which lack lung tissue, to investigate the role of CFTR in cardiogenesis. Our findings demonstrated that the loss of CFTR impairs cardiac development from the cardiac progenitor stage, resulting in cardiac looping defects, a dilated atrium, pericardial edema, and a decrease in heart rate. Furthermore, we found that cardiac development was perturbed in wild-type embryos treated with a gating-specific CFTR channel inhibitor, CFTRinh-172, at the blastula stage of development, but not at later stages. Gene expression analysis of blastulas indicated that transcript levels, including mRNAs associated with cardiovascular diseases, were significantly altered in embryos derived from cftr mutants relative to controls. To evaluate the role of CFTR in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found that the I556V mutation in CFTR, which causes a channel defect, was associated with the disease. Similar to other well-studied channel-defective CFTR mutants, CFTR I556V mRNA failed to restore cardiac dysplasia in mutant embryos. The present study revealed an important role for the CFTR ion channel in regulating cardiac development during early embryogenesis, supporting the hypothesis that CF-related heart disease results from an intrinsic primary defect in the heart.
被引量：2 发表：1970
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Following the intracellular localization of the iab-8ncRNA of the bithorax complex using the MS2-MCP-GFP system.
Homeotic genes are aligned on the chromosome in the order of the segments that they specify along the antero-posterior axis of the fly. In general the genes affecting the more posterior segments repress the more anterior genes, a phenomenon known as "posterior dominance". There is however a noticeable exception to this rule in the central nervous system of Drosophila melanogaster where the posterior Abd-B gene does not repress the immediately more anterior abd-A gene. Instead, abd-A repression is accomplished by a 92 kb-long ncRNA (the iab-8ncRNA) that is transcribed from the large inter-genic region between abd-A and Abd-B. This iab-8ncRNA encodes a microRNA to repress abd-A and also a second redundant repression mechanism acting in cis and thought to be transcriptional interference with the abd-A promoter. Using in situ hybridization, a previous work suggested that the iab8ncRNA transcript forms discrete foci restricted to the nuclear periphery and that this localization may be important for its function. In order to better characterize the intra-cellular localization of the iab-8ncRNA we used the MS2-MCP system, which allows fluorescent labeling of RNA in cells and relies on the interaction between GFP-tagged MS2 coat protein (MCP-GFP) and MS2 RNA stem loops. Our results indicate that the large foci seen in previous studies correspond to the site of iab8ncRNA transcription and that the foci seen may simply be an indication of the level of transcription at the locus. We find no evidence to suggest that this localization is important for its function on abd-A repression. We discuss the idea that the iab-8ncRNA may be a relic of a more general ancient mechanism of posterior dominance during the emergence of the hox clusters that was mediated by transcriptional interference.
被引量：3 发表：1970
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Gbx2 functions as a transcriptional repressor to regulate the specification and morphogenesis of the mid-hindbrain junction in a dosage- and stage-dependent manner.
The Gbx subfamily of homeodomain transcription factors is involved in the positioning of the isthmus, which patterns the midbrain and cerebellum in vertebrates. To uncover the details of Gbx functions, we first examined the dose dependency of its effects on brain formation in zebrafish and found that high-dose gbx2 mRNA injection affected the entire forebrain and midbrain, whereas low-dose mRNA specifically disrupted the isthmic folding at the midbrain-hindbrain boundary (MHB) but only weakly affected the expression of genes involved in MHB specification. Thus, isthmus morphogenesis, and not its early specification, is highly sensitive to gbx2. Transient induction of heat-inducible gbx2 using transgenic fish showed that MHB specification is most sensitive to gbx2 at the end of epiboly and further suggested that otx2 is the direct target gene. These together demonstrate that gbx2 regulates both specification and morphogenesis of the MHB/isthmus region. Deletion analyses showed that both the N- and C-terminal regions contribute to the suppressive activity of Gbx2 against the anterior brain and that the N-terminal core region, including the Eh1 and proline-rich sequences, is required for this Gbx2 activity. Comparison of the effects of activated and repressive forms with wild-type Gbx2 suggested that Gbx2 functions as a transcriptional repressor, which was further evidenced by a luciferase assay in which gbx2 repressed the MHB enhancer of fgf8a in mouse P19 cells.
被引量：7 发表：1970
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Modifying transcript lengths of cycling mouse segmentation genes.
Regular production of somites, precursors of the axial skeleton and attached muscles is controlled by a molecular oscillator, the segmentation clock, which drives cyclic transcription of target genes in the unsegmented presomitic mesoderm (PSM). The clock is based on a negative feedback loop which generates pulses of transcription that oscillate with the same periodicity as somite formation. Mutants in several oscillating genes including the Notch pathway gene Lunatic fringe (Lfng) and the Notch target Hes7, result in defective somitogenesis and disorganised axial skeletons. Both genes encode negative regulators of Notch signalling output, but it is not yet clear if they are just secondary clock targets or if they encode components of a primary, pacemaker oscillator. In this paper, we try to identify components in the primary oscillator by manipulating delays in the feedback circuitry. We characterise recombinant mice in which Lfng and Hes7 introns are lengthened in order to delay mRNA production. Lengthening the third Hes7 intron by 10 or 20 kb disrupts accurate RNA splicing and inactivates the gene. Lfng expression and activity is normal in mice whose Lfng is lengthened by 10 kb, but no effects on segmentation are evident. We discuss these results in terms of the relative contributions of transcriptional and post-transcriptional delays towards defining the pace of segmentation, and of alternative strategies for manipulating the period of the clock.
被引量：5 发表：1970
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Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells.
The study of how human embryonic stem cells (hESCs) differentiate into insulin-producing beta cells has twofold significance: first, it provides an in vitro model system for the study of human pancreatic development, and second, it serves as a platform for the ultimate production of beta cells for transplantation into patients with diabetes. The delineation of growth factor interactions regulating pancreas specification from hESCs in vitro is critical to achieving these goals. In this study, we describe the roles of growth factors bFGF, BMP4 and Activin A in early hESC fate determination. The entire differentiation process is carried out in serum-free chemically-defined media (CDM) and results in reliable and robust induction of pancreatic endoderm cells, marked by PDX1, and cell clusters co-expressing markers characteristic of beta cells, including PDX1 and insulin/C-peptide. Varying the combinations of growth factors, we found that treatment of hESCs with bFGF, Activin A and BMP4 (FAB) together for 3-4days resulted in strong induction of primitive-streak and definitive endoderm-associated genes, including MIXL1, GSC, SOX17 and FOXA2. Early proliferative foregut endoderm and pancreatic lineage cells marked by PDX1, FOXA2 and SOX9 expression are specified in EBs made from FAB-treated hESCs, but not from Activin A alone treated cells. Our results suggest that important tissue interactions occur in EB-based suspension culture that contribute to the complete induction of definitive endoderm and pancreas progenitors. Further differentiation occurs after EBs are embedded in Matrigel and cultured in serum-free media containing insulin, transferrin, selenium, FGF7, nicotinamide, islet neogenesis associated peptide (INGAP) and exendin-4, a long acting GLP-1 agonist. 21-28days after embedding, PDX1 gene expression levels are comparable to those of human islets used for transplantation, and many PDX1(+) clusters are formed. Almost all cells in PDX1(+) clusters co-express FOXA2, HNF1ß, HNF6 and SOX9 proteins, and many cells also express CPA1, NKX6.1 and PTF1a. If cells are then switched to medium containing B27 and nicotinamide for 7-14days, then the number of insulin(+) cells increases markedly. Our study identifies a new chemically defined culture protocol for inducing endoderm- and pancreas-committed cells from hESCs and reveals an interplay between FGF, Activin A and BMP signaling in early hESC fate determination.
被引量：68 发表：1970
