oalib
Search Results: 1 - 10 of 100 matches for " "
All listed articles are free for downloading (OA Articles)
Page 1 /100
Display every page Item
The Gene Regulatory Cascade Linking Proneural Specification with Differentiation in Drosophila Sensory Neurons  [PDF]
Sebastián Cachero,T. Ian Simpson,Petra I. zur Lage,Lina Ma,Fay G. Newton,Eimear E. Holohan,J. Douglas Armstrong,Andrew P. Jarman
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000568
Abstract: In neurogenesis, neural cell fate specification is generally triggered by proneural transcription factors. Whilst the role of proneural factors in fate specification is well studied, the link between neural specification and the cellular pathways that ultimately must be activated to construct specialised neurons is usually obscure. High-resolution temporal profiling of gene expression reveals the events downstream of atonal proneural gene function during the development of Drosophila chordotonal (mechanosensory) neurons. Among other findings, this reveals the onset of expression of genes required for construction of the ciliary dendrite, a key specialisation of mechanosensory neurons. We determine that atonal activates this cellular differentiation pathway in several ways. Firstly, atonal directly regulates Rfx, a well-known highly conserved ciliogenesis transcriptional regulator. Unexpectedly, differences in Rfx regulation by proneural factors may underlie variations in ciliary dendrite specialisation in different sensory neuronal lineages. In contrast, fd3F encodes a novel forkhead family transcription factor that is exclusively expressed in differentiating chordotonal neurons. fd3F regulates genes required for specialized aspects of chordotonal dendrite physiology. In addition to these intermediate transcriptional regulators, we show that atonal directly regulates a novel gene, dilatory, that is directly associated with ciliogenesis during neuronal differentiation. Our analysis demonstrates how early cell fate specification factors can regulate structural and physiological differentiation of neuronal cell types. It also suggests a model for how subtype differentiation in different neuronal lineages may be regulated by different proneural factors. In addition, it provides a paradigm for how transcriptional regulation may modulate the ciliogenesis pathway to give rise to structurally and functionally specialised ciliary dendrites.
The Gene Regulatory Cascade Linking Proneural Specification with Differentiation in Drosophila Sensory Neurons  [PDF]
Sebastián Cachero equal contributor,T. Ian Simpson equal contributor,Petra I. zur Lage equal contributor,Lina Ma,Fay G. Newton,Eimear E. Holohan,J. Douglas Armstrong,Andrew P. Jarman
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1000568
Abstract: In neurogenesis, neural cell fate specification is generally triggered by proneural transcription factors. Whilst the role of proneural factors in fate specification is well studied, the link between neural specification and the cellular pathways that ultimately must be activated to construct specialised neurons is usually obscure. High-resolution temporal profiling of gene expression reveals the events downstream of atonal proneural gene function during the development of Drosophila chordotonal (mechanosensory) neurons. Among other findings, this reveals the onset of expression of genes required for construction of the ciliary dendrite, a key specialisation of mechanosensory neurons. We determine that atonal activates this cellular differentiation pathway in several ways. Firstly, atonal directly regulates Rfx, a well-known highly conserved ciliogenesis transcriptional regulator. Unexpectedly, differences in Rfx regulation by proneural factors may underlie variations in ciliary dendrite specialisation in different sensory neuronal lineages. In contrast, fd3F encodes a novel forkhead family transcription factor that is exclusively expressed in differentiating chordotonal neurons. fd3F regulates genes required for specialized aspects of chordotonal dendrite physiology. In addition to these intermediate transcriptional regulators, we show that atonal directly regulates a novel gene, dilatory, that is directly associated with ciliogenesis during neuronal differentiation. Our analysis demonstrates how early cell fate specification factors can regulate structural and physiological differentiation of neuronal cell types. It also suggests a model for how subtype differentiation in different neuronal lineages may be regulated by different proneural factors. In addition, it provides a paradigm for how transcriptional regulation may modulate the ciliogenesis pathway to give rise to structurally and functionally specialised ciliary dendrites.
Multiple enhancers contribute to spatial but not temporal complexity in the expression of the proneural gene, amos
Eimear E Holohan, Petra I zur Lage, Andrew P Jarman
BMC Developmental Biology , 2006, DOI: 10.1186/1471-213x-6-53
Abstract: Amos protein expression has a complex pattern and shows temporally distinct phases, in common with previously characterised proneural genes. GFP reporter gene constructs were used to demonstrate that amos has an array of enhancer elements up- and downstream of the gene, which are required for different locations of amos expression. However, unlike other proneural genes, there is no evidence for separable enhancers for the different temporal phases of amos expression. Using mutant analysis and site-directed mutagenesis of potential Amos binding sites, we find no evidence for positive autoregulation as an important part of amos control during neurogenesis.For amos, as for other proneural genes, a complex expression pattern results from the sum of a number of simpler sub-patterns driven by specific enhancers. There is, however, no apparent separation of enhancers for distinct temporal phases of expression, and this correlates with a lack of positive autoregulation. For scute and atonal, both these features are thought to be important in the mechanism of neurogenesis. Despite similarities in function and expression between the Drosophila proneural genes, amos is regulated in a fundamentally different way from scute and atonal.Proneural genes are key regulators of neurogenesis. They encode transcription factors of the basic-helix-loop-helix (bHLH) family whose expression endows ectodermal cells with competence to become neural precursors. For the Drosophila PNS, the proneural genes achaete (ac), scute (sc), atonal (ato) and amos are required for the precursors of different subsets of sense organs and sensory neurons (sense organ precursors, SOPs) [1-8]. Each is expressed in a complex ectodermal pattern that prefigures the formation of these subsets of SOPs. SOPs/sense organs are missing in loss of function mutants, whereas ectopic proneural gene expression results in induction of ectopic SOPs/sense organs.Given their powerful effects in neurogenesis, it is not surprising
The function and regulation of the bHLH gene, cato, in Drosophila neurogenesis
Petra I zur Lage, Andrew P Jarman
BMC Developmental Biology , 2010, DOI: 10.1186/1471-213x-10-34
Abstract: We characterised the expression pattern of cato in detail using newly raised antibodies and GFP reporter gene constructs. Expression is predominantly in sensory lineages that depend on the atonal and amos proneural genes. In lineages that depend on the scute proneural gene, cato is expressed later and seems to be particularly associated with the type II neurons. Consistent with this, we find evidence that cato is a direct target gene of Atonal and Amos, but not of Scute. We generated two specific mutations of cato. Mutant embryos show several defects in chordotonal sensory lineages, most notably the duplication of the sensory neuron, which appears to be caused by an extra cell division. In addition, we show that cato is required to form the single chordotonal organ that persists in atonal mutant embryos.We conclude that although widely expressed in the developing PNS, cato is expressed and regulated very differently in different sensory lineages. Mutant phenotypes correlate with cato's major expression in the chordotonal sensory lineage. In these cells, we propose that it plays roles in sense organ precursor maintenance and/or identity, and in controlling the number of cell divisions in the neuronal branch of the lineage arising from these precursors.Basic-helix-loop-helix (bHLH) transcription factors are central to neurogenesis in metazoans [1]. The most well known role for such factors in neurogenesis is the so-called 'proneural' function. This function underlies the commitment of neuroectodermal cells to a neural fate, and the term comes originally from the study of proneural genes in Drosophila. In this organism, proneural genes include atonal (ato), amos, scute (sc), and achaete (ac) which are required for the specification of sense organ precursors (SOPs) of the peripheral nervous system [2]. In mutations of these genes, specific subsets of SOPs fail to be formed. For instance, ato is required for the formation of SOPs of chordotonal (Ch) proprioceptive sensor
Atonal homolog 1 Is a Tumor Suppressor Gene  [PDF]
Wouter Bossuyt,Avedis Kazanjian,Natalie De Geest,Sofie Van Kelst,Gert De Hertogh,Karel Geboes,Greg P. Boivin,Judith Luciani,Francois Fuks,Marinee Chuah,Thierry VandenDriessche,Peter Marynen,Jan Cools,Noah F. Shroyer,Bassem A. Hassan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000039
Abstract: Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation.
Atonal homolog 1 Is a Tumor Suppressor Gene  [PDF]
Wouter Bossuyt equal contributor,Avedis Kazanjian equal contributor,Natalie De Geest,Sofie Van Kelst,Gert De Hertogh,Karel Geboes,Greg P Boivin,Judith Luciani,Francois Fuks,Marinee Chuah,Thierry VandenDriessche,Peter Marynen,Jan Cools,Noah F Shroyer ,Bassem A Hassan
PLOS Biology , 2009, DOI: 10.1371/journal.pbio.1000039
Abstract: Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation.
atonal- and achaete-scute-related genes in the annelid Platynereis dumerilii: insights into the evolution of neural basic-Helix-Loop-Helix genes
Elena Simionato, Pierre Kerner, Nicolas Dray, Martine Le Gouar, Valérie Ledent, Detlev Arendt, Michel Vervoort
BMC Evolutionary Biology , 2008, DOI: 10.1186/1471-2148-8-170
Abstract: We have studied Platynereis orthologs of the most important vertebrate neural bHLH genes, i.e. achaete-scute, neurogenin, atonal, olig, and NeuroD genes, the latter two being genes absent of the Drosophila genome. We observed that all these genes have specific expression patterns during nervous system formation in Platynereis. Our data suggest that in Platynereis, like in vertebrates but unlike Drosophila, (i) neurogenin is the main proneural gene for the formation of the trunk central nervous system, (ii) achaete-scute and olig genes are involved in neural subtype specification in the central nervous system, in particular in the specification of the serotonergic phenotype. In addition, we found that the Platynereis NeuroD gene has a broad and early neuroectodermal expression, which is completely different from the neuronal expression of vertebrate NeuroD genes.Our analysis suggests that the Platynereis bHLH genes have both proneural and neuronal specification functions, in a way more akin to the vertebrate situation than to that of Drosophila. We conclude that these features are ancestral to bilaterians and have been conserved in the vertebrates and annelids lineages, but have diverged in the evolutionary lineage leading to Drosophila.Neurogenesis is a complex process that involves the formation of a vast array of neuronal and glial cell types that must be produced in the correct numbers and at appropriate positions. Genetic and molecular studies mainly conducted in Drosophila and vertebrates have shown that genes encoding transcription factors of the basic Helix-Loop-Helix (bHLH) class play pivotal roles in various steps of neurogenesis, including commitment of neural precursors (proneural function), specification of particular neuronal identities, and neuronal differentiation [1-5]. Most of the genes encoding bHLH transcription factors and which are involved in neural development (hereafter named neural bHLH genes), belong to five of the numerous phylogenetically
Integrating Computational Biology and Forward Genetics in Drosophila  [PDF]
Stein Aerts equal contributor,Sven Vilain equal contributor,Shu Hu equal contributor,Leon-Charles Tranchevent equal contributor,Roland Barriot,Jiekun Yan,Yves Moreau,Bassem A. Hassan ,Xiao-Jiang Quan equal contributor
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000351
Abstract: Genetic screens are powerful methods for the discovery of gene–phenotype associations. However, a systems biology approach to genetics must leverage the massive amount of “omics” data to enhance the power and speed of functional gene discovery in vivo. Thus far, few computational methods for gene function prediction have been rigorously tested for their performance on a genome-wide scale in vivo. In this work, we demonstrate that integrating genome-wide computational gene prioritization with large-scale genetic screening is a powerful tool for functional gene discovery. To discover genes involved in neural development in Drosophila, we extend our strategy for the prioritization of human candidate disease genes to functional prioritization in Drosophila. We then integrate this prioritization strategy with a large-scale genetic screen for interactors of the proneural transcription factor Atonal using genomic deficiencies and mutant and RNAi collections. Using the prioritized genes validated in our genetic screen, we describe a novel genetic interaction network for Atonal. Lastly, we prioritize the whole Drosophila genome and identify candidate gene associations for ten receptor-signaling pathways. This novel database of prioritized pathway candidates, as well as a web application for functional prioritization in Drosophila, called Endeavour-HighFly, and the Atonal network, are publicly available resources. A systems genetics approach that combines the power of computational predictions with in vivo genetic screens strongly enhances the process of gene function and gene–gene association discovery.
Robust Target Gene Discovery through Transcriptome Perturbations and Genome-Wide Enhancer Predictions in Drosophila Uncovers a Regulatory Basis for Sensory Specification  [PDF]
Stein Aerts,Xiao-Jiang Quan,Annelies Claeys,Marina Naval Sanchez,Phillip Tate,Jiekun Yan,Bassem A. Hassan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000435
Abstract: A comprehensive systems-level understanding of developmental programs requires the mapping of the underlying gene regulatory networks. While significant progress has been made in mapping a few such networks, almost all gene regulatory networks underlying cell-fate specification remain unknown and their discovery is significantly hampered by the paucity of generalized, in vivo validated tools of target gene and functional enhancer discovery. We combined genetic transcriptome perturbations and comprehensive computational analyses to identify a large cohort of target genes of the proneural and tumor suppressor factor Atonal, which specifies the switch from undifferentiated pluripotent cells to R8 photoreceptor neurons during larval development. Extensive in vivo validations of the predicted targets for the proneural factor Atonal demonstrate a 50% success rate of bona fide targets. Furthermore we show that these enhancers are functionally conserved by cloning orthologous enhancers from Drosophila ananassae and D. virilis in D. melanogaster. Finally, to investigate cis-regulatory cross-talk between Ato and other retinal differentiation transcription factors (TFs), we performed motif analyses and independent target predictions for Eyeless, Senseless, Suppressor of Hairless, Rough, and Glass. Our analyses show that cisTargetX identifies the correct motif from a set of coexpressed genes and accurately predicts target genes of individual TFs. The validated set of novel Ato targets exhibit functional enrichment of signaling molecules and a subset is predicted to be coregulated by other TFs within the retinal gene regulatory network.
Robust Target Gene Discovery through Transcriptome Perturbations and Genome-Wide Enhancer Predictions in Drosophila Uncovers a Regulatory Basis for Sensory Specification  [PDF]
Stein Aerts ,Xiao-Jiang Quan,Annelies Claeys,Marina Naval Sanchez,Phillip Tate,Jiekun Yan,Bassem A. Hassan
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000435
Abstract: A comprehensive systems-level understanding of developmental programs requires the mapping of the underlying gene regulatory networks. While significant progress has been made in mapping a few such networks, almost all gene regulatory networks underlying cell-fate specification remain unknown and their discovery is significantly hampered by the paucity of generalized, in vivo validated tools of target gene and functional enhancer discovery. We combined genetic transcriptome perturbations and comprehensive computational analyses to identify a large cohort of target genes of the proneural and tumor suppressor factor Atonal, which specifies the switch from undifferentiated pluripotent cells to R8 photoreceptor neurons during larval development. Extensive in vivo validations of the predicted targets for the proneural factor Atonal demonstrate a 50% success rate of bona fide targets. Furthermore we show that these enhancers are functionally conserved by cloning orthologous enhancers from Drosophila ananassae and D. virilis in D. melanogaster. Finally, to investigate cis-regulatory cross-talk between Ato and other retinal differentiation transcription factors (TFs), we performed motif analyses and independent target predictions for Eyeless, Senseless, Suppressor of Hairless, Rough, and Glass. Our analyses show that cisTargetX identifies the correct motif from a set of coexpressed genes and accurately predicts target genes of individual TFs. The validated set of novel Ato targets exhibit functional enrichment of signaling molecules and a subset is predicted to be coregulated by other TFs within the retinal gene regulatory network.
Page 1 /100
Display every page Item


Home
Copyright © 2008-2017 Open Access Library. All rights reserved.