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Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Research Institute Molecular Pathol IMP, Vienna.
University of Vienna.
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2012 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 10, no 3, e1001280- p.Article in journal (Refereed) Published
Abstract [en]

The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system.

Place, publisher, year, edition, pages
Public Library of Science , 2012. Vol. 10, no 3, e1001280- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-76960DOI: 10.1371/journal.pbio.1001280ISI: 000302239700004OAI: oai:DiVA.org:liu-76960DiVA: diva2:524000
Note
Funding Agencies|Marie Curie Actions (European Commission)||Swedish Research Council||Swedish Strategic Research Foundation||Boehringer Ingelheim GmbH||DFG||Schram-Foundation||Available from: 2012-04-27 Created: 2012-04-27 Last updated: 2017-12-07
In thesis
1. Mechanisms of sensory neuron diversification during development and in the adult Drosophila: How to make a difference
Open this publication in new window or tab >>Mechanisms of sensory neuron diversification during development and in the adult Drosophila: How to make a difference
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The nervous system contains a vast number of neurons and displays a great diversity in cell types and classes. Even though this has been known for a long time, the exact mechanism of cell specification is still poorly understood. How does a cell know what type of neuron to which it should be specified? It is important to understand cellular specification, not only for our general understanding of biological processes, but also to allow us to develop treatments for patients with destructive diseases, such as Alzheimer’s, Parkinson, cancer or stroke. To address how neuronal specification and thereby diversification is evolved, we have chosen to study a complex but defined set of neurons, the Drosophila olfactory system. Olfactory sensory neurons (OSNs) detect an enormous variety of small volatile molecules with extremely high specificity and sensitivity. The adult Drosophila olfactory system contains 34 OSN classes each defined by their expression of a specific odorant receptor (OR). In both insects and vertebrates, each OSN expresses only one OR. In mouse there are approximately 1200 and in Drosophila 60 different OR genes. Despite the range of mechanisms known to determine cell identity and that the olfactory system is remarkably conserved across the phyla, it is still unclear how an OSN chooses to express a particular OR from a large genomic repertoire. In this thesis, the specification and diversification of the final steps establishing an OSN identity is addressed. We find seven transcription factors that are continuously required in different combinations for the expression of all ORs. The TFs can in different gene context both activate and repress OR expression, making the regulation more economical and indicating that repression is crucial for correct gene expression. We further identified a repressor complex that is able to segregate OR expression between OSN classes and propose a mechanism on how one single co-repressor can specify a large number of neuron classes.Exploring the OSN we found the developmental Hh signalling pathway is expressed in the postmitotic neuron. We show several fundamental similarities between the canonical Drosophila Hh pathway and the cilia mediated Hh transduction in component function. Further investigation revealed a function of cilia mediated Hh signalling in sensory neuron modulator. The results generated here will create a greater in vivo understanding of how postmitotic processes generate neurons with different fates and contribute to the maintaining of neuron function.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 68 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1390
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104706 (URN)10.3384/diss.diva-104706 (DOI)978-91-7519-428-8 (ISBN)
Public defence
2014-03-21, Berszeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2016-12-28Bibliographically approved
2. Mechanisms of Olfactory sensory neuron class maintenance in Drosophila: It is all about design and equilibrium
Open this publication in new window or tab >>Mechanisms of Olfactory sensory neuron class maintenance in Drosophila: It is all about design and equilibrium
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

How the cellular diversity of our body is generated and maintained is still a great mystery regardless of the wealth of research that has been done on this issue. The greatest complexity is found in the nervous system that contains a vast number of neurons and displays a great diversity in cell types and classes. For example the Drosophila olfactory system is a complex but defined set of neurons with extremely high specificity and sensitivity. The 34 OSN classes are each defined by their expression of a specific odorant receptor (OR). During development each OSN chooses one OR from 60 different OR genes in the genome to express. Furthermore, a cell is subject to immense challenges during its life cycle. Confronting each challenge the cell needs to perform its function and maintain its fate. OSNs continue to express the same OR during their  whole life regardless of fluctuations in the environment.

Although the olfactory system is remarkably conserved across the phyla, it is still unclear how an OSN chooses to express a particular OR from a large genomic repertoire. In this thesis the final steps of the specification and diversification for establishing an OSN identity is addressed. We find seven transcription factors that are continuously required in different combinations for the expression of the Drosophila ORs. The TFs can in different background context both activate and repress OR expression, making the regulation more economical. We also imply that repression is crucial for correct OR gene expression. We further show that short DNA sequences from OR gene promoters are sufficient to drive OSN class specific expression. These regions contain clusters of TF binding motifs, which we show to be sensitive to any change in their composition or to changes of the internal or external environment. We demonstrate that the chromatin state is responsible for the clusters response to environmental challenges. We reveal that Su(var)3-9 controls the OSN response to environmental stresses. We address the epigenetic mechanisms that initiate and pertain the single OR expression to a single OSN class. Our results show that OSNs have an epigenetic switch marking the end of development and the transition to mature OSNs. This switch supplies the expression of a single OR gene.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 66 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1458
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-120992 (URN)10.3384/diss.diva-120992 (DOI)978-91-7519-085-3 (ISBN)
Public defence
2015-09-04, Berszeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-02 Created: 2015-09-01 Last updated: 2016-11-30Bibliographically approved

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Jafari, ShadiAlkhori, LizaAlenius, Mattias

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