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Yaghmaeian Salmani, B., Monedero Cobeta, I., Rakar, J., Bauer, S., Rodriguez Curt, J., Starkenberg, A. & Thor, S. (2018). Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program. Development, 145(7), Article ID dev160747.
Open this publication in new window or tab >>Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program
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2018 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev160747Article in journal (Refereed) Published
Abstract [en]

A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions.

Place, publisher, year, edition, pages
Cambridge, United Kingdom: The Company of Biologists Ltd., 2018
Keywords
Asymmetric division, Cell cycle, Combinatorial control, Evolution of the CNS, Lineage size, Nervous system development
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-147741 (URN)10.1242/dev.160747 (DOI)000438944000010 ()29530878 (PubMedID)2-s2.0-85045513794 (Scopus ID)
Available from: 2018-05-09 Created: 2018-05-09 Last updated: 2018-12-10Bibliographically approved
Monedero, I., Bivik, C., Li, J., Yu, P., Thor, S. & Benito-Sipos, J. (2018). Specification of Drosophila neuropeptidergic neurons by the splicing component brr2. PLoS Genetics, 14(8), Article ID e1007496.
Open this publication in new window or tab >>Specification of Drosophila neuropeptidergic neurons by the splicing component brr2
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2018 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 8, article id e1007496Article in journal (Refereed) Published
Abstract [en]

During embryonic development, a number of genetic cues act to generate neuronal diversity. While intrinsic transcriptional cascades are well-known to control neuronal sub-type cell fate, the target cells can also provide critical input to specific neuronal cell fates. Such signals, denoted retrograde signals, are known to provide critical survival cues for neurons, but have also been found to trigger terminal differentiation of neurons. One salient example of such target-derived instructive signals pertains to the specification of the Drosophila FMRFamide neuropeptide neurons, the Tv4 neurons of the ventral nerve cord. Tv4 neurons receive a BMP signal from their target cells, which acts as the final trigger to activate the FMRFa gene. A recent FMRFa-eGFP genetic screen identified several genes involved in Tv4 specification, two of which encode components of the U5 subunit of the spliceosome: brr2 (l(3) 72Ab) and Prp8. In this study, we focus on the role of RNA processing during target- derived signaling. We found that brr2 and Prp8 play crucial roles in controlling the expression of the FMRFa neuropeptide specifically in six neurons of the VNC (Tv4 neurons). Detailed analysis of brr2 revealed that this control is executed by two independent mechanisms, both of which are required for the activation of the BMP retrograde signaling pathway in Tv4 neurons: (1) Proper axonal pathfinding to the target tissue in order to receive the BMP ligand. (2) Proper RNA splicing of two genes in the BMP pathway: the thickveins (tkv) gene, encoding a BMP receptor subunit, and the Medea gene, encoding a co-Smad. These results reveal involvement of specific RNA processing in diversifying neuronal identity within the central nervous system.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2018
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-151518 (URN)10.1371/journal.pgen.1007496 (DOI)000443389100005 ()30133436 (PubMedID)
Note

Funding Agencies|Ministerio de Economia y competitividad [BFU2016-78327-P]; Swedish Research Council [621-2010-5214]; Knut and Alice Wallenberg Foundation [KAW2011.0165]; Swedish Cancer Foundation [100351]

Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2019-03-13
Bivik, C., Macdonald, R., Gunnar, E., Mazouni, K., Schweisguth, F. & Thor, S. (2016). Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling. PLoS Genetics, 12(4), Article ID e1005984.
Open this publication in new window or tab >>Control of Neural Daughter Cell Proliferation by Multi-level Notch/Su(H)/E(spl)-HLH Signaling
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2016 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 4, article id e1005984Article in journal (Refereed) Published
Abstract [en]

The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-128759 (URN)10.1371/journal.pgen.1005984 (DOI)000375231900032 ()27070787 (PubMedID)
Note

Funding Agencies|Knut and Alice Wallenberg Foundation [KAW2012.0101]; Swedish Research Council [621-2010-5214]; Swedish Cancer Foundation [120531]

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2019-03-13
Gabilondo, H., Stratmann, J., Rubio-Ferrera, I., Millan-Crespo, I., Contero-Garcia, P., Bahrampour, S., . . . Benito-Sipos, J. (2016). Neuronal Cell Fate Specification by the Convergence of Different Spatiotemporal Cues on a Common Terminal Selector Cascade. PLoS biology, 14(5), e1002450
Open this publication in new window or tab >>Neuronal Cell Fate Specification by the Convergence of Different Spatiotemporal Cues on a Common Terminal Selector Cascade
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2016 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 14, no 5, p. e1002450-Article in journal (Refereed) Published
Abstract [en]

Specification of the myriad of unique neuronal subtypes found in the nervous system depends upon spatiotemporal cues and terminal selector gene cascades, often acting in sequential combinatorial codes to determine final cell fate. However, a specific neuronal cell subtype can often be generated in different parts of the nervous system and at different stages, indicating that different spatiotemporal cues can converge on the same terminal selectors to thereby generate a similar cell fate. However, the regulatory mechanisms underlying such convergence are poorly understood. The Nplp1 neuropeptide neurons in the Drosophila ventral nerve cord can be subdivided into the thoracic-ventral Tv1 neurons and the dorsal-medial dAp neurons. The activation of Nplp1 in Tv1 and dAp neurons depends upon the same terminal selector cascade: colamp;gt;ap/eyaamp;gt;dimmamp;gt;Nplp1. However, Tv1 and dAp neurons are generated by different neural progenitors (neuroblasts) with different spatiotemporal appearance. Here, we find that the same terminal selector cascade is triggered by Kr/pdmamp;gt;grn in dAp neurons, but by Antp/hth/exd/lbe/cas in Tv1 neurons. Hence, two different spatiotemporal combinations can funnel into a common downstream terminal selector cascade to determine a highly related cell fate.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2016
National Category
Developmental Biology
Identifiers
urn:nbn:se:liu:diva-129501 (URN)10.1371/journal.pbio.1002450 (DOI)000376906100001 ()27276273 (PubMedID)
Note

Funding Agencies|Swedish Research Council (VR-NT) [621-2010-5214]; Wallenberg Foundation [KAW2012.0101]; Swedish Cancer Foundation [120531]; Spanish Ministerio de Economia y Competitividad [BFU2013-43858-P]

Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2017-11-28
Bivik, C., Bahrampour, S., Ulvklo, C., Nilsson, P., Angel, A., Fransson, F., . . . Thor, S. (2015). Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells. Genetics, 200(4), 1229-1244
Open this publication in new window or tab >>Novel Genes Involved in Controlling Specification of Drosophila FMRFamide Neuropeptide Cells
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2015 (English)In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 200, no 4, p. 1229-1244Article in journal (Refereed) Published
Abstract [en]

The expression of neuropeptides is often extremely restricted in the nervous system, making them powerful markers for addressing cell specification . In the developing Drosophila ventral nerve cord, only six cells, the Ap4 neurons, of some 10,000 neurons, express the neuropeptide FMRFamide (FMRFa). Each Ap4/FMRFa neuron is the last-born cell generated by an identifiable and well-studied progenitor cell, neuroblast 5-6 (NB5-6T). The restricted expression of FMRFa and the wealth of information regarding its gene regulation and Ap4 neuron specification makes FMRFa a valuable readout for addressing many aspects of neural development, i.e., spatial and temporal patterning cues, cell cycle control, cell specification, axon transport, and retrograde signaling. To this end, we have conducted a forward genetic screen utilizing an Ap4-specific FMRFa-eGFP transgenic reporter as our readout. A total of 9781 EMS-mutated chromosomes were screened for perturbations in FMRFa-eGFP expression, and 611 mutants were identified. Seventy-nine of the strongest mutants were mapped down to the affected gene by deficiency mapping or whole-genome sequencing. We isolated novel alleles for previously known FMRFa regulators, confirming the validity of the screen. In addition, we identified novel essential genes, including several with previously undefined functions in neural development. Our identification of genes affecting most major steps required for successful terminal differentiation of Ap4 neurons provides a comprehensive view of the genetic flow controlling the generation of highly unique neuronal cell types in the developing nervous system.

Place, publisher, year, edition, pages
Genetics Society of America, 2015
Keywords
Drosophila; CNS development; neural cell fate specification; forward genetic screening; FMRFamide
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-121318 (URN)10.1534/genetics.115.178483 (DOI)000359917000020 ()26092715 (PubMedID)
Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2019-03-13Bibliographically approved
Jonsson, M., Pokrzywa, M., Starkenberg, A., Hammarström, P. & Thor, S. (2015). Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues. PLoS ONE, 10(7), Article ID e0133272.
Open this publication in new window or tab >>Systematic A beta Analysis in Drosophila Reveals High Toxicity for the 1-42, 3-42 and 11-42 Peptides, and Emphasizes N- and C-Terminal Residues
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133272Article in journal (Refereed) Published
Abstract [en]

Brain amyloid plaques are a hallmark of Alzheimers disease (AD), and primarily consist of aggregated A beta peptides. While A beta 1-40 and A beta 1-42 are the most abundant, a number of other A beta peptides have also been identified. Studies have indicated differential toxicity for these various A beta peptides, but in vivo toxicity has not been systematically tested. To address this issue, we generated improved transgenic Drosophila UAS strains expressing 11 pertinent A beta peptides. UAS transgenic flies were generated by identical chromosomal insertion, hence removing any transgenic position effects, and crossed to a novel and robust Gal4 driver line. Using this improved Gal4/UAS set-up, survival and activity assays revealed that A beta 1-42 severely shortens lifespan and reduces activity. N-terminal truncated peptides were quite toxic, with 3-42 similar to 1-42, while 11-42 showed a pronounced but less severe phenotype. N-terminal mutations in 3-42 (E3A) or 11-42 (E11A) resulted in reduced toxicity for 11-42, and reduced aggregation for both variants. Strikingly, C-terminal truncation of A beta (1-41, -40, -39, -38, -37) were non-toxic. In contrast, C-terminal extension to 1-43 resulted in reduced lifespan and activity, but not to the same extent as 1-42. Mutating residue 42 in 1-42 (A42D, A42R and A42W) greatly reduced A beta accumulation and toxicity. Histological and biochemical analysis revealed strong correlation between in vivo toxicity and brain A beta aggregate load, as well as amount of insoluble A beta. This systematic Drosophila in vivo and in vitro analysis reveals crucial N- and C-terminal specificity for A beta neurotoxicity and aggregation, and underscores the importance of residues 1-10 and E11, as well as a pivotal role of A42.

Place, publisher, year, edition, pages
Public Library of Science, 2015
National Category
Chemical Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120740 (URN)10.1371/journal.pone.0133272 (DOI)000358622000074 ()26208119 (PubMedID)
Note

Funding Agencies|Swedish VINNOVA; King Gustaf Vs and Queen Victorias Freemasons Foundation; AstraZeneca, Sodertalje; Swedish Research Council; VINNOVA grant, "Innovations for future health"

Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2018-04-25
Allan, D. W. & Thor, S. (2015). Transcriptional selectors, masters, and combinatorial codes: regulatory principles of neural subtype specification. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY, 4(5), 505-528
Open this publication in new window or tab >>Transcriptional selectors, masters, and combinatorial codes: regulatory principles of neural subtype specification
2015 (English)In: WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY, ISSN 1759-7684, Vol. 4, no 5, p. 505-528Article, review/survey (Refereed) Published
Abstract [en]

The broad range of tissue and cellular diversity of animals is generated to a large extent by the hierarchical deployment of sequence-specific transcription factors and co-factors (collectively referred to as TFs herein) during development. Our understanding of these developmental processes has been facilitated by the recognition that the activities of many TFs can be meaningfully described by a few functional categories that usefully convey a sense for how the TFs function, and also provides a sense for the regulatory organization of the developmental processes in which they participate. Here, we draw on examples from studies in Caenorhabditis elegans, Drosophila melanogaster, and vertebrates to discuss how the terms spatial selector, temporal selector, tissue/cell type selector, terminal selector and combinatorial code may be usefully applied to categorize the activities of TFs at critical steps of nervous system construction. While we believe that these functional categories are useful for understanding the organizational principles by which TFs direct nervous system construction, we however caution against the assumption that a TFs function can be solely or fully defined by any single functional category. Indeed, most TFs play diverse roles within different functional categories, and their roles can blur the lines we draw between these categories. Regardless, it is our belief that the concepts discussed here are helpful in clarifying the regulatory complexities of nervous system development, and hope they prove useful when interpreting mutant phenotypes, designing future experiments, and programming specific neuronal cell types for use in therapies.

Place, publisher, year, edition, pages
Wiley, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120857 (URN)10.1002/wdev.191 (DOI)000359429900004 ()25855098 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Knut and Alice Wallenberg Foundation; Swedish Cancer Foundation; Swedish Royal Academy of Sciences; Canadian Institutes of Health Research; National Sciences and Engineering Research Council of Canada

Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2016-11-30
Baumgardt, M., Karlsson, D., Yaghmaeian Salmani, B., Bivik, C., MacDonald, R., Gunnar, E. & Thor, S. (2014). Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade. Developmental Cell, 30(2), 192-208
Open this publication in new window or tab >>Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
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2014 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 30, no 2, p. 192-208Article in journal (Refereed) Published
Abstract [en]

During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential. Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood. We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0). This typelgreater than0 switch is triggered by activation of Dacapo (mammalian p21(CIP1)/p27(KIP1)/p57(Kip2)) expression in neuroblasts. In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia. In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f. This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS.

Place, publisher, year, edition, pages
Elsevier (Cell Press), 2014
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-109588 (URN)10.1016/j.devcel.2014.06.021 (DOI)000339641500012 ()25073156 (PubMedID)
Available from: 2014-08-21 Created: 2014-08-21 Last updated: 2019-03-13
Losada-Perez, M., Gabilondo, H., Molina, I., Turiegano, E., Torroja, L., Thor, S. & Benito-Sipos, J. (2013). Klumpfuss controls FMRFamide expression by enabling BMP signaling within the NB5-6 lineage. Development, 140(10), 2181-2189
Open this publication in new window or tab >>Klumpfuss controls FMRFamide expression by enabling BMP signaling within the NB5-6 lineage
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2013 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 140, no 10, p. 2181-2189Article in journal (Refereed) Published
Abstract [en]

A number of transcription factors that are expressed within most, if not all, embryonic neuroblast (NB) lineages participate in neural subtype specification. Some have been extensively studied in several NB lineages (e.g. components of the temporal gene cascade) whereas others only within specific NB lineages. To what extent they function in other lineages remains unknown. Klumpfuss (Klu), the Drosophila ortholog of the mammalian Wilms tumor 1 (WT1) protein, is one such transcription factor. Studies in the NB4-2 lineage have suggested that Klu functions to ensure that the two ganglion mother cells (GMCs) in this embryonic NB lineage acquire different fates. Owing to limited lineage marker availability, these observations were made only for the NB4-2 lineage. Recent findings reveal that Klu is necessary for larval neuroblast growth and self-renewal. We have extended the study of Klu to the well-known embryonic NB5-6T lineage and describe a novel role for Klu in the Drosophila embryonic CNS. Our results demonstrate that Klu is expressed specifically in the postmitotic Ap4/FMRFa neuron, promoting its differentiation through the initiation of BMP signaling. Our findings indicate a pleiotropic function of Klu in Ap cluster specification in general and particularly in Ap4 neuron differentiation, indicating that Klu is a multitasking transcription factor. Finally, our studies indicate that a transitory downregulation of klu is crucial for the specification of the Ap4/FMRFa neuron. Similar to WT1, klu seems to have either self-renewal or differentiation-promoting functions, depending on the developmental context.

Place, publisher, year, edition, pages
Company of Biologists, 2013
Keywords
Drosophila, Klumpfuss, Terminal differentiation, BMP signaling, Neuropeptidergic cell identity, FMRFa
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-93857 (URN)10.1242/dev.089748 (DOI)000318273900013 ()
Note

Funding Agencies|Spanish Ministerio de Ciencia e Innovacion|BFU-2008-04683-C02-02|Swedish Research Council||Swedish Strategic Research Foundation||Knut and Alice Wallenberg Foundation||Swedish Brain Foundation||Swedish Cancer Foundation||Swedish Royal Academy of Sciences||

Available from: 2013-06-11 Created: 2013-06-11 Last updated: 2017-12-06
Thor, S. (2013). Neuroscience: Stem cells in multiple time zones. Nature, 498(7455), 441-443
Open this publication in new window or tab >>Neuroscience: Stem cells in multiple time zones
2013 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 498, no 7455, p. 441-443Article in journal, Editorial material (Other academic) Published
Abstract [en]

In fruitfly larvae, neural stem cells generate different cell types at different times. It emerges that these temporal progressions are controlled by multiple cascades of gene transcription factors.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-95822 (URN)10.1038/nature12261 (DOI)000320929400039 ()
Available from: 2013-07-26 Created: 2013-07-26 Last updated: 2017-12-06Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5095-541x

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