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Mechanisms of sensory neuron diversification during development and in the adult Drosophila: How to make a difference
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-104706DOI: 10.3384/diss.diva-104706ISBN: 978-91-7519-428-8 (print)OAI: oai:DiVA.org:liu-104706DiVA: diva2:698630
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
List of papers
1. Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
Open this publication in new window or tab >>Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression
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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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76960 (URN)10.1371/journal.pbio.1001280 (DOI)000302239700004 ()
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
2. The corepressor Atrophin specifies odorant receptor expression in Drosophila
Open this publication in new window or tab >>The corepressor Atrophin specifies odorant receptor expression in Drosophila
2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 3, 1355-1364 p.Article in journal (Refereed) Published
Abstract [en]

In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.

Place, publisher, year, edition, pages
Federation of American Societies for Experimental Biology, 2014
Keyword
HDAC, Notch, epigenetic, neuronal differentiation, olfactory system
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104702 (URN)10.1096/fj.13-240325 (DOI)000335324800027 ()24334704 (PubMedID)
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2017-12-05Bibliographically approved
3. Cilia-Mediated Hedgehog Signaling in Drosophila
Open this publication in new window or tab >>Cilia-Mediated Hedgehog Signaling in Drosophila
2014 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 7, no 3, 672-680 p.Article in journal (Refereed) Published
Abstract [en]

Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-107115 (URN)10.1016/j.celrep.2014.03.052 (DOI)000335560900009 ()
Note

At the time for thesis presentation publication was in status: Manuscript

Available from: 2014-06-05 Created: 2014-06-05 Last updated: 2017-12-05Bibliographically approved
4. Hh signalling regulates odorant receptor cilia localization in Drosophila
Open this publication in new window or tab >>Hh signalling regulates odorant receptor cilia localization in Drosophila
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Hedgehog (Hh) signaling is a key regulatory pathway during development. Here, we show that in adult OSNs the Hh pathway regulate 􀁒dorant receptor transport to cilia and put forward a novel non-developmental function of the pathway as a neuromodulator. We demonstrate that the level of Hh signal modulate the OSNs response to odors. We show that knock down of Hh and Smoothened (Smo), a transmembrane protein that transduce the signal, are required for receptor transport. We further show that the coreceptor, Orco, has an Hh independent transport path and that knock down of Smo segregate OR and Orco to different vesicular compartments. Last, we show that the odor response to the second receptor type in Drosophila olfaction, the ionotropic receptors (IRs), also require Hh signalling. Thus, Hh signalling is a general regulator of the odorant response that fulfils the criteria of being a potential player in Drosophila odorant adaptation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104705 (URN)
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2014-02-24Bibliographically approved

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