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Alenius, Mattias
Alternative names
Publications (10 of 19) 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
Jafari, S. & Alenius, M. (2015). Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila. PLOS Genetics, 11(3), e1005051
Open this publication in new window or tab >>Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila
2015 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 3, p. e1005051-Article in journal (Refereed) Published
Abstract [en]

Odor perception requires that each olfactory sensory neuron (OSN) class continuously express a single odorant receptor (OR) regardless of changes in the environment. However, little is known about the control of the robust, class-specific OR expression involved. Here, we investigate the cis-regulatory mechanisms and components that generate robust and OSN class-specific OR expression in Drosophila. Our results demonstrate that the spatial restriction of expression to a single OSN class is directed by clusters of transcription-factor DNA binding motifs. Our dissection of motif clusters of differing complexity demonstrates that structural components such as motif overlap and motif order integrate transcription factor combinations and chromatin status to form a spatially restricted pattern. We further demonstrate that changes in metabolism or temperature perturb the function of complex clusters. We show that the cooperative regulation between motifs around and within the cluster generates robust, class-specific OR expression.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117811 (URN)10.1371/journal.pgen.1005051 (DOI)000352197100039 ()25760344 (PubMedID)
Note

Funding Agencies|Swedish Foundation for Strategic Research [F06-0013]; Swedish Research Council [522-2006-6364 / K2007-66P-20436-01-04]

Available from: 2015-05-11 Created: 2015-05-08 Last updated: 2017-12-04
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
Öst, A., Lempradl, A., Casas, E., Weigert, M., Tiko, T., Deniz, M., . . . Pospisilik, J. A. (2014). Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity. Cell, 159(6), 1352-1364
Open this publication in new window or tab >>Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity
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2014 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, no 6, p. 1352-1364Article in journal (Refereed) Published
Abstract [en]

The global rise in obesity has revitalized a search for genetic and epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced intergenerational metabolic reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as 2 days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, desilencing chromatin-state-defined domains in both mature sperm and in offspring embryos. We identify requirements for H3K9/K27me3-dependent reprogramming of metabolic genes in two distinct germline and zygotic windows. Critically, we find evidence that a similar system may regulate obesity susceptibility and phenotype variation in mice and humans. The findings provide insight into the mechanisms underlying intergenerational metabolic reprogramming and carry profound implications for our understanding of phenotypic variation and evolution.

Place, publisher, year, edition, pages
Elsevier (Cell Press), 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113500 (URN)10.1016/j.cell.2014.11.005 (DOI)000346652900014 ()25480298 (PubMedID)
Note

Funding Agencies|Max-Planck Society; EU (NoE Epigenesys); ERC [281641]; Swedish VR [K2011-78PK-21893-01-2]; SSMF grants; Spanish Ministry grant [BFU2011-30246, RYC-2010-07114]; Marie Curie European Reintegration Grant "Evo-Chromo; IMPPC; Champalimaud Foundation; Human Frontiers Program Project Grant [RGP0022/2012]; Portuguese Foundation for Science and Technology (FCT) grant [PTDC/BIA-BCM/118684/2010]; Foundation for Science and Technology [SFRH/BPD/79325/2011]

Available from: 2015-01-19 Created: 2015-01-19 Last updated: 2017-12-05
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
Neely, G. G., Hess, A., Costigan, M., Keene, A. C., Goulas, S., Langeslag, M., . . . Penninger, J. M. (2010). A Genome-wide Drosophila Screen for Heat Nociception Identifies alpha 2 delta 3 as an Evolutionarily Conserved Pain Gene. CELL, 143(4), 628-638
Open this publication in new window or tab >>A Genome-wide Drosophila Screen for Heat Nociception Identifies alpha 2 delta 3 as an Evolutionarily Conserved Pain Gene
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2010 (English)In: CELL, ISSN 0092-8674, Vol. 143, no 4, p. 628-638Article in journal (Refereed) Published
Abstract [en]

Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the alpha 2 delta family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (alpha 2 delta 3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, alpha 2 delta 3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in alpha 2 delta 3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in alpha 2 delta 3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-62750 (URN)10.1016/j.cell.2010.09.047 (DOI)000284149100019 ()
Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2010-12-03
Schultz, S., Gu, X., Rusten, T. E., Alenius, M. & Westermark, G. (2010). HIAPP and hproIAPP triggers elective autophagy and inhibit the neuro-­protective effect of autophagy. , 17
Open this publication in new window or tab >>HIAPP and hproIAPP triggers elective autophagy and inhibit the neuro-­protective effect of autophagy
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2010 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Amyloid formation is associated with cell death and islet amyloid is thought to participate in the 50-60% β-cell reduction detected in patients with type 2 diabetes. Islet amyloid polypeptide (IAPP) is the main amyloid protein in the islets of Langerhans. Initial IAPP-amyloid formation is intracellular and part of this amyloid constitutes of proIAPP.

Material & methods: We have established a new model in Drosophila melanogaster where expression of hproIAPP and IAPP results in the formation of amyloid. With this model, we have investigated the effect of protein aggregation on pathways such as ER-stress, unfolded protein response (UPR), apoptosis and autophagy. Important steps in the different pathways were manipulated by RNAi-technique or over- expression of endogenous Drosophila proteins.

Results: Expression of hproIAPP and hIAPP driven to the pdf-neurons led to cell death, but this was without activation of ER-stress, UPR or apoptosis. Aggregated hproIAPP and IAPP, labeled with antibodies against ubiquitin and p62 were accumulated intracellular, a finding that points to an involvement of autophagy. HproIAPP and hIAPP were shown to exert their toxic activity by an intracellular mechanism in contrary to Aβ42 and Aβ42 E22G that exhibit an extracellular toxic activity.

Conclusion: Studies on toxicity suggest that hproIAPP and hIAPP aggregates can occupy the autophagy pathway and prevent maintenance of basal cellular homeostasis. Comparison of proIAPP/IAPP and Aβ42 toxicity shows that amyloid proteins of separate origin can exhibit different toxicity.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70093 (URN)
Available from: 2011-08-18 Created: 2011-08-18 Last updated: 2011-08-18Bibliographically approved
Keleman, K., Kruettner, S., Alenius, M. & Dickson, B. J. (2007). Function of the Drosophila CPEB protein Orb2 in long-term courtship memory. Nature Neuroscience, 10(12), 1587-1593
Open this publication in new window or tab >>Function of the Drosophila CPEB protein Orb2 in long-term courtship memory
2007 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 10, no 12, p. 1587-1593Article in journal (Refereed) Published
Abstract [en]

Both long-term behavioral memory and synaptic plasticity require protein synthesis, some of which may occur locally at specific synapses. Cytoplasmic polyadenylation element-binding (CPEB) proteins are thought to contribute to the local protein synthesis that underlies long-term changes in synaptic efficacy, but a role has not been established for them in the formation of long-term behavioral memory. We found that the Drosophila melanogaster CPEB protein Orb2 is acutely required for long-term conditioning of male courtship behavior. Deletion of the N-terminal glutamine-rich region of Orb2 resulted in flies that were impaired in their ability to form long-term, but not short-term, memory. Memory was restored by expressing Orb2 selectively in fruitless (fru)positive c neurons of the mushroom bodies and by providing Orb2 function in mushroom bodies only during and shortly after training. Our data thus demonstrate that a CPEB protein is important in long-term memory and map the molecular, spatial and temporal requirements for its function in memory formation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2007
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59693 (URN)10.1038/nn1996 (DOI)000251172900016 ()
Available from: 2010-09-23 Created: 2010-09-23 Last updated: 2017-12-12
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