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Author: Wui-Chuong Jen
Publisher:
ISBN:
Category :
Languages : en
Pages : 318
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Author: Wui-Chuong Jen
Publisher:
ISBN:
Category :
Languages : en
Pages : 318
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Author: Meaghan Ebetino
Publisher:
ISBN:
Category :
Languages : en
Pages : 44
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Abstract: Somitogenesis is an embryological process regulated by the Notch signaling pathway. Somites are the precursors to the vertebrae and ribs and they bud from the pre-somitic mesoderm (PSM). This process is regulated by a clock that times the process and by mechanisms that regulate somite patterning. Mutations in the Notch pathway perturb both the clock and patterning activities during somitogenesis and disrupt normal skeletal development. Lunatic fringe (Lfng), a Notch family member, plays separable roles in the clock and patterning mechanisms during somitogenesis. Loss of Lfng in mice results in malformed vertebrae, truncated tails, and fused ribs. This phenotype is also seen in mice lacking Deltalike3 (Dll3), an unusual Notch ligand. Furthermore, mutations in either Dll3 or Lfng can be responsible for the disease spondylocostal dysostosis in humans, which is characterized by disorganized ribs and vertebrae. These similarities suggest that Dll3 and Lfng may have overlapping roles during somitogenesis. However, many open questions remain about Dll3's role during somitogenesis and Notch signaling: (1) Is Dll3 an inhibitor or activator of Notch? (2) Does Dll3 play important roles in the clock or patterning activities of Notch signaling or both? (3) Do Lfng and Dll3 act together or separately during Notch signaling? To determine if Dll3 is an activator or inhibitor of Notch, we are examining the activation of the Notch receptor and the expression of Notch target genes in Dll3 null (Dll3pu/pu) embryos. To dissect the roles played by Dll3 in the clock and in somite patterning, a transgene was designed to specifically drive Dll3 expression in the patterning of somites but not within the clock. Experiments are underway to assay the expression of the transgenes in the PSM of embryos. Finally, to examine the potential functional overlaps between Lfng and Dll3, double heterozygous mice for Dll3 and Lfng (Dll3 +/pu; Lfng +/- ) and homozygous null mice for Dll3 and Lfng (Dll3 pu/pu; Lfng -/- ) are being examined for unique skeletal phenotypes. The results from these studies suggest that Dll3 and Lfng do not have overlapping roles during Notch signaling.
Author: Stacey P. Contakos
Publisher:
ISBN:
Category : Developmental biology
Languages : en
Pages : 214
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Author: Maurisa Flynn Riley
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Abstract: The Notch pathway is a highly conserved signaling mechanism used for cell-to-cell communication during development. Errors in this communication system can lead to birth defects and contribute to the development and progression of numerous diseases. The significance of Notch in cardiac development is evident from the identification of human mutations in various Notch pathway members that result in congenital cardiovascular malformations. Despite the importance of Notch signaling in cardiac development, a lack of functional studies examining the molecular mechanisms underlying these Notch implicated malformations represents a significant gap in the field of cardiovascular biology. We identified novel NOTCH1 mutations in patients with cardiac malformations involving the left ventricular outflow tract (LVOT) that reduce ligand-induced signaling through defective intracellular processing of the mutant Notch1 receptor protein. The Notch pathway also functions in a biological clock that is critical for skeletal development during somitogenesis. During somitogenesis, somites bud from the anterior end of the presomitic mesoderm (PSM) to give rise to the axial skeleton, the dermis of the back, and skeletal muscle. This developmental process proves useful for studying the Notch pathway, because in the PSM, Notch oscillations are coordinated, resulting in visible oscillatory expression of genes linked to the clock. Mutations that perturb these oscillations can be easily observed at the level of gene expression, and result in overt skeletal phenotypes that do not affect viability. Proper clock function requires that gene expression of Notch pathway members be tightly controlled during the time period of the clock. One of these oscillatory genes is Lunatic fringe (Lfng), which encodes a glycosyltransferase that modifies the Notch receptor to modulate Notch signaling (Hicks C, 2000). Understanding the mechanisms of Notch regulation in the segmentation clock is an active topic of research with many unanswered questions. We hypothesized that microRNAs (miRNAs), small molecules that regulate gene expression, have a conserved function in the segmentation clock through regulation of oscillatory genes in the Notch pathway. miRNA microarray analysis and RT-PCR identified miRNAs enriched in the mouse PSM. Preventing interactions between one of these miRNAs, miR-125a-5p, and Lfng in vivo leads to abnormal segmentation and perturbs cyclic gene expression in the PSM, indicating that miRNA regulation of Lfng is important for the clock mechanism. This work provides the first evidence supporting a role for miRNAs in the segmentation clock and reveals a novel mechanism of post-transcriptional regulation of oscillatory genes. In addition, since the miRNA microarray revealed a large number of miRNAs either enriched in the PSM or mature somites, future work in the lab will examine the function of these miRNAs in segmentation clock function and somite maturation.
Author: Hans Meinhardt
Publisher:
ISBN:
Category : Science
Languages : en
Pages : 252
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Author: Timothy J. Mead
Publisher:
ISBN:
Category :
Languages : en
Pages : 237
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Congenital malformations are the most common cause of infant death in the United States. Skeletal and neural crest related structures, including cardiac outflow tract and craniofacial disorders, make up the majority of these malformations. Therefore, identifying molecular mechanisms that regulate skeletal and cardiac development is of great clinical importance. The Notch signaling pathway has been implicated in cell fatespecification, migration, proliferation, and differentiation in a variety of cell types and organs and mis-expression of Notch signaling results in disease and associated malformations. Skeletogenesis encompasses several processes including somitogenesis, chondrogenesis, and osteogenesis that contribute to proper skeletal development. Notch signaling is necessary for proper somitogenesis and osteogenesis, but the role of Notch signaling in chondrogenesis in vivo was unknown. The studies detailed here demonstrate that Notch signaling is required for proper cartilageprogenitor proliferation and hypertrophic chondrocyte differentiation in the axial and appendicular skeleton. During development, neural crest cells (NCCs) are formed in the dorsal neural tube and subsequently migrate, proliferate, and differentiate into a multitude of derivatives and structures including craniofacial and cardiac outflow tractderivatives. Notch signaling is also active in the neural crest and derivatives, but the mechanisms of Notch function at specific stages and developmental processes in NCC are unknown. Studies detailed in this dissertation demonstrate critical cell-autonomous roles for appropriate levels of Notch signaling during NCC migration, proliferation anddifferentiation with critical implications in craniofacial, cardiac, and neurogenic development and disease.
Author: Malgorzata Kloc
Publisher: John Wiley & Sons
ISBN: 1118492811
Category : Science
Languages : en
Pages : 459
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Frogs from the genus Xenopus have long been used as model organisms in basic and biomedical research. These frogs have helped unlock key fundamental developmental and cellular processes that have led to important scientific breakthroughs and have had practical application in embryology, cancer research and regenerative medicine. Xenopus Development is a vital resource on the biology and development of these key model organisms, and will be a great tool to researchers using these frogs in various disciplines of biological science. Xenopus Development is divided into four sections, the first three highlight key processes in Xenopus development from embryo to metamophosis. These sections focus on the cellular processes, organogenesis and embryo development. The final section highlights novel techniques and approaches being used in Xenopus research. Providing thorough and detailed coverage, Xenopus Development, will be a timely and welcome volume for those working in cell and molecular biology, genetics, developmental biology and biomedical research. Provides broad overview of the developmental biology of both Xenopus laevis and Xenopus tropicalis Explores cellular to systems development in key biomedical model organisms Timely synthesis of the field of Xenopus biology Highlights key biomedical and basic biological findings unlocked by Xenopus
Author: Mark E. Pownall
Publisher:
ISBN:
Category : Cellular signal transduction
Languages : en
Pages :
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Embryonic development is a robust process during which embryos must respond and compensate for changes in order to achieve consistent patterning; however, there are still questions about the limits and mechanisms of this robustness. Using tetraploid Xenopus laevis as a model, we have previously shown that embryos respond to perturbations of the highly-conserved Notch signaling pathway in a compensatory manner. We have now demonstrated that this response involves changes in the proliferative status of neural progenitors and differentiated neurons over time. Subsequent RNA-seq analysis of Notch perturbed X. laevis embryos revealed that homeologs (duplicated genes originating from whole-genome duplication) respond differentially to this perturbation, suggesting that the polyploidy of X. laevis may contribute to the compensatory abilities. To address this question, we have perturbed Notch signaling in X. borealis, a tetraploid species that is closely related to X. laevis, and characterized the response over time. Similarly to X. laevis, a compensatory response is seen in X. borealis over time based on gene expression in the developing nervous system, but embryos appear morphologically deformed throughout development. This suggests that X. borealis embryos may be more severely affected by this perturbation and do not compensate as well as X. laevis. RNA-seq was performed on Notch perturbed X. borealis embryos to quantitatively and globally assess the transcriptional response over time. Given that there was previously no reference genome or transcriptome for X. borealis, a de novo assembly of the X. borealis transcriptome was constructed to allow for further analysis. Using the X. laevis genome as a reference has allowed for comparative analysis of the changes in homeolog expression in X. laevis and X. borealis embryos following Notch perturbation. These data have revealed differences in the response to Notch perturbation between X. borealis and X. laevis, with X. borealis generally having more differentially expressed genes when compared to X. laevis under the same condition, again suggesting that X. borealis is more severely perturbed and does not compensate as well as X. laevis. To validate and compliment these RNA-seq results, it would be ideal to visualize homeolog expression in situ; however, given the high degree of sequence homology between homeologs, detection of specific homeolog transcripts in situ has presented a challenge for traditional methods. Using two new in situ hybridization technologies (Molecular Instruments Hybridization Chain Reaction v3.0 and Advanced Cell Diagnostics BaseScopeTM assay), we have been able to visualize X. laevis homeolog expression in situ with extreme specificity, which will enable spatial analysis of homeolog expression and a tool to validate RNA-seq findings. In the future, it will be interesting compare the transcriptional response to Notch signaling perturbation across ploidy levels, in addition to within multiple tetraploid species as we have already done. To enable this type of comparative experiment, we have sequenced and assembled the transcriptome of Xenopus andrei, an octoploid frog, representing, to the best of our knowledge, the first publicly available assembled transcriptome of an octoploid vertebrate.
Author: Pieter D. Nieuwkoop
Publisher: Garland Science
ISBN: 9780815318965
Category : Medical
Languages : en
Pages : 252
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Book Description
A Systematical and Chronological Survey of the Development from the Fertilized Egg till the End of Metomorphosis
Author: Ruth Bellairs
Publisher: Springer Science & Business Media
ISBN: 1489920137
Category : Science
Languages : en
Pages : 318
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Book Description
Somite development is a unique and important topic; unique because somitic mesoderm is the first tissue to become segmented, important because the somites - once established - exert a profound influence on other seg mental structures which form later. Somite development is of interest at a number of levels. In one aspect, demarcation of a specific number of somites and size regulation, it is a particularly intriguing example of embryonic pattern formation, 'especially in vew of its possible relation to homoeobox-controlled segmentation in insects. At another level, somite development has long been studied by compara tive anatomists, but only recently has new light been thrown on such sub jects as segmentation of the head, proposed in the 18th century by Goethe and now a live issue for developmental biologists. Somit es are simple when they first appear, but very complex structures arise from them. These include the vertebrae and the axial and other muscles and consequently there is a wealth of morphogenetic problems to be explored. Sometimes their morphogenesis is disturbed, by genetic or environ mental factors, and there are many clinical conditions which arise as a result.
