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  • 01/2014; 4. DOI:10.1016/j.coviro.2014.01.001
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    ABSTRACT: Using high-resolution live imaging in zebrafish, we show that presumptive eye cells acquire apicobasal polarity and adopt neuroepithelial character prior to other regions of the neural plate. Neuroepithelial organization is first apparent at the margin of the eye field, whereas cells at its core have mesenchymal morphology. These core cells subsequently intercalate between the marginal cells contributing to the bilateral expansion of the optic vesicles. During later evagination, optic vesicle cells shorten, drawing their apical surfaces laterally relative to the basal lamina, resulting in further laterally directed evagination. The early neuroepithelial organization of the eye field requires Laminin1, and ectopic Laminin1 can redirect the apicobasal orientation of eye field cells. Furthermore, disrupting cell polarity through combined abrogation of the polarity protein Pard6γb and Laminin1 severely compromises optic vesicle evagination. Our studies elucidate the cellular events underlying early eye morphogenesis and provide a framework for understanding epithelialization and complex tissue formation.
    Developmental Cell 10/2013; 27(3). DOI:10.1016/j.devcel.2013.09.023
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    ABSTRACT: Manipulation of gene expression on a genome-wide level is one of the most important systematic tools in the post-genome era. Such manipulations have largely been enabled by expression cloning approaches using sequence-verified cDNA libraries, large-scale RNA interference libraries (shRNA or siRNA) and zinc finger nuclease technologies. More recently, the CRISPR (clustered regularly interspaced short palindromic repeats) and CRISPR-associated (Cas)9-mediated gene editing technology has been described that holds great promise for future use of this technology in genomic manipulation. It was suggested that the CRISPR system has the potential to be used in high-throughput, large-scale loss of function screening. Here we discuss some of the challenges in engineering of CRISPR/Cas genomic libraries and some of the aspects that need to be addressed in order to use this technology on a high-throughput scale.
    Frontiers in Genetics 10/2013; 4:193. DOI:10.3389/fgene.2013.00193
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    ABSTRACT: Understanding how a functional organ can be produced from a small group of cells remains an outstanding question in cell and developmental biology. The developing compound eye of Drosophila has long been a model of choice for addressing this question by dissecting the cellular, genetic and molecular pathways that govern cell specification, differentiation, and multicellular patterning during organogenesis. In this review, I focus on cell and tissue morphogenesis during fly retinal development, including the regulated changes in cell shape and cell packing that ultimately determine the shape and architecture of the compound eye. In particular, I review recent studies that highlight the prominent roles of transcriptional and hormonal controls that orchestrate the cell shape changes, cell-cell junction remodeling and polarized membrane growth that underlie photoreceptor morphogenesis and retinal patterning.
    Developmental Biology 10/2013; DOI:10.1016/j.ydbio.2013.09.031
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    ABSTRACT: Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs) are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1(-/-) mSCs redifferentiate normally, whereas at the wound site Nf1(-/-) mSCs give rise to neurofibromas in both Nf1(+/+) and Nf1(+/-) backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.
    Cell Reports 09/2013; DOI:10.1016/j.celrep.2013.08.033
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    ABSTRACT: An adult animal consists of cells of vastly different size and activity, but the regulation of cell size remains poorly understood. Recent studies uncovering some of the signaling pathways important for size/growth control, together with the identification of diseases resulting from aberrations in these pathways, have renewed interest in this field. This Review will discuss our current understanding of how a cell sets its size, how it can adapt its size to a changing environment, and how these processes are relevant to human disease.
    Cell 09/2013; 154(6):1194-205. DOI:10.1016/j.cell.2013.08.053
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    ABSTRACT: In eukaryotic cells, detection of replication stress results in the activation of the DNA replication checkpoint, a signaling cascade whose central players are the kinases ATR and Chk1. The checkpoint response prevents the accumulation of DNA damage and ensures cell viability by delaying progression into mitosis. However, the role and mechanism of the replication checkpoint transcriptional response in human cells, which is p53 independent, is largely unknown. We show that, in response to DNA replication stress, the regular E2F-dependent cell-cycle transcriptional program is maintained at high levels, and we establish the mechanisms governing such transcriptional upregulation. E2F6, a repressor of E2F-dependent G1/S transcription, replaces the activating E2Fs at promoters to repress transcription in cells progressing into S phase in unperturbed conditions. After replication stress, the checkpoint kinase Chk1 phosphorylates E2F6, leading to its dissociation from promoters. This promotes E2F-dependent transcription, which mediates cell survival by preventing DNA damage and cell death. This work reveals, for the first time, that the regular cell-cycle transcriptional program is part of the DNA replication checkpoint response in human cells and establishes the molecular mechanism involved. We show that maintaining high levels of G1/S cell-cycle transcription in response to replication stress contributes to two key functions of the DNA replication checkpoint response, namely, preventing genomic instability and cell death. Given the critical role of replication stress in oncogene transformation, a detailed understanding of the molecular mechanisms involved in the checkpoint response will contribute to a better insight into cancer development.
    Current biology: CB 08/2013; 23(17). DOI:10.1016/j.cub.2013.06.063
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    ABSTRACT: In neurons, the timely and accurate expression of genes in response to synaptic activity relies on the interplay between epigenetic modifications of histones, recruitment of regulatory proteins to chromatin and changes to nuclear structure. To identify genes and regulatory elements responsive to synaptic activation in vivo, we performed a genome-wide ChIPseq analysis of acetylated histone H3 using somatosensory cortex of mice exposed to novel enriched environmental (NEE) conditions. We discovered that Short Interspersed Elements (SINEs) located distal to promoters of activity-dependent genes became acetylated following exposure to NEE and were bound by the general transcription factor TFIIIC. Importantly, under depolarizing conditions, inducible genes relocated to transcription factories (TFs), and this event was controlled by TFIIIC. Silencing of the TFIIIC subunit Gtf3c5 in non-stimulated neurons induced uncontrolled relocation to TFs and transcription of activity-dependent genes. Remarkably, in cortical neurons, silencing of Gtf3c5 mimicked the effects of chronic depolarization, inducing a dramatic increase of both dendritic length and branching. These findings reveal a novel and essential regulatory function of both SINEs and TFIIIC in mediating gene relocation and transcription. They also suggest that TFIIIC may regulate the rearrangement of nuclear architecture, allowing the coordinated expression of activity-dependent neuronal genes.
    PLoS Genetics 08/2013; 9(8):e1003699. DOI:10.1371/journal.pgen.1003699
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    ABSTRACT: The accurate transition from G1 phase of the cell cycle to S phase is crucial for the control of eukaryotic cell proliferation, and its misregulation promotes oncogenesis. During G1 phase, growth-dependent cyclin-dependent kinase (CDK) activity promotes DNA replication and initiates G1-to-S phase transition. CDK activation initiates a positive feedback loop that further increases CDK activity, and this commits the cell to division by inducing genome-wide transcriptional changes. G1-S transcripts encode proteins that regulate downstream cell cycle events. Recent work is beginning to reveal the complex molecular mechanisms that control the temporal order of transcriptional activation and inactivation, determine distinct functional subgroups of genes and link cell cycle-dependent transcription to DNA replication stress in yeast and mammals.
    Nature Reviews Molecular Cell Biology 08/2013; 14(8):518-28. DOI:10.1038/nrm3629
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    ABSTRACT: The Flower protein family is part of a cell-cell communication pathway that regulates cell competition, in which fit cells eliminate less fit neighbors. A new study demonstrates that this pathway can also govern the culling of unwanted neurons during development.
    Current biology: CB 07/2013; 23(14):R613-5. DOI:10.1016/j.cub.2013.06.036
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