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Alkhori, Liza
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Publications (8 of 8) Show all publications
Sanchez, G. M., Alkhori Franzén, L., Hatano, E., Schultz, S., Kuzhandaivel, A., Jafari, S., . . . Alenius, M. (2016). Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila. Cell reports, 14(3), 464-470
Open this publication in new window or tab >>Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 3, p. 464-470Article in journal (Refereed) Published
Abstract [en]

Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.

Place, publisher, year, edition, pages
CELL PRESS, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125311 (URN)10.1016/j.celrep.2015.12.059 (DOI)000368701600008 ()26774485 (PubMedID)
Note

Funding Agencies|Swedish Foundation for Strategic Research [F06-0013]

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2018-03-23
Kuzhandaivel, A., Schultz, S., Alkhori, L. & Alenius, M. (2014). Cilia-Mediated Hedgehog Signaling in Drosophila. Cell reports, 7(3), 672-680
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, p. 672-680Article 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
Alkhori, L., Sanchez, G. M., Schultz, S. W., Kuzhandaivel, A., Granseth, B. & Alenius, M. (2014). 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: 2018-01-25Bibliographically approved
Alkhori, L. (2014). Mechanisms of sensory neuron diversification during development and in the adult Drosophila: How to make a difference. (Doctoral dissertation). Linköping: Linköping University Electronic Press
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. p. 68
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
Alkhori, L., Öst, A. & Alenius, M. (2014). The corepressor Atrophin specifies odorant receptor expression in Drosophila. The FASEB Journal, 28(3), 1355-1364
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, p. 1355-1364Article 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
Keywords
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
Jafari, S., Alkhori, L., Schleiffer, A., Brochtrup, A., Hummel, T. & Alenius, M. (2012). Combinatorial Activation and Repression by Seven Transcription Factors Specify Drosophila Odorant Receptor Expression. PLoS biology, 10(3), e1001280
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, p. e1001280-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
Bjartmar, L., Alkhori, L., Ruud, J., Marcusson, J. & Hallbeck, M. (2010). Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula. Brain Research, 1328, 24-33
Open this publication in new window or tab >>Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula
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2010 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1328, p. 24-33Article in journal (Refereed) Published
Abstract [en]

Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, is involved in activity-dependent synaptogenesis and synaptic plasticity. In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. This study demonstrates that NP2 mRNA is robustly expressed in the hippocampus and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is enhanced in the hippocampal subregions as well as in the MHb after long-term treatment with antidepressant drugs of various monoaminergic profiles, indicating a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant induced plasticity, but not EE induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.

Place, publisher, year, edition, pages
Elsevier, 2010
Keywords
Neuronal pentraxins, narp, habenula, hippocampus, synaptic plasticity, antidepressant
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-51408 (URN)10.1016/j.brainres.2010.03.004 (DOI)000277682400003 ()
Note
On the day of the defence day the status of this article was: Submitted.Available from: 2009-10-30 Created: 2009-10-30 Last updated: 2017-12-12Bibliographically approved
Pérez-Tenorio, G., Alkhori, L., Olsson, B., Ahnstro Waltersson, M., Nordenskjöld, B., Rutqvist, L. E., . . . Stål, O. (2007). PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clinical Cancer Research, 13(12), 3577-3584
Open this publication in new window or tab >>PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
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2007 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 12, p. 3577-3584Article in journal (Refereed) Published
Abstract [en]

Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15041 (URN)10.1158/1078-0432.CCR-06-1609 (DOI)17575221 (PubMedID)
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2017-12-11
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