umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
von Hofsten, Jonas
Alternative names
Publications (10 of 25) Show all publications
Tran, P., Wanrooij, P. H., Lorenzon, P., Sharma, S., Thelander, L., Nilsson, A. K., . . . Chabes, A. (2019). De novo dNTP production is essential for normal postnatal murine heart development. Journal of Biological Chemistry, Article ID jbc.RA119.009492.
Open this publication in new window or tab >>De novo dNTP production is essential for normal postnatal murine heart development
Show others...
2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, article id jbc.RA119.009492Article in journal (Refereed) Epub ahead of print
Abstract [en]

The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in wild-type postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in wildtype hearts.

Keywords
cardiac function, cardiac muscle, dNTP metabolism, dNTP salvage, deoxyribonucleoside kinases, desmin, heart development, nucleoside/nucleotide biosynthesis, nucleoside/nucleotide metabolism, ribonucleotide reductase
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161767 (URN)10.1074/jbc.RA119.009492 (DOI)31300555 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-08-06
Nord, H., Dennhag, N., Tydinger, H. & von Hofsten, J. (2019). The zebrafish HGF receptor met controls migration of myogenic progenitor cells in appendicular development. PLoS ONE, 14(7), Article ID e0219259.
Open this publication in new window or tab >>The zebrafish HGF receptor met controls migration of myogenic progenitor cells in appendicular development
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 7, article id e0219259Article in journal (Refereed) Published
Abstract [en]

The hepatocyte growth factor receptor C-met plays an important role in cellular migration, which is crucial for many developmental processes as well as for cancer cell metastasis. Cmet has been linked to the development of mammalian appendicular muscle, which are derived from migrating muscle progenitor cells (MMPs) from within the somite. Mammalian limbs are homologous to the teleost pectoral and pelvic fins. In this study we used Crispr/Cas9 to mutate the zebrafish met gene and found that the MMP derived musculature of the paired appendages was severely affected. The mutation resulted in a reduced muscle fibre number, in particular in the pectoral abductor, and in a disturbed pectoral fin function. Other MMP derived muscles, such as the sternohyoid muscle and posterior hypaxial muscle were also affected in met mutants. This indicates that the role of met in MMP function and appendicular myogenesis is conserved within vertebrates.

Place, publisher, year, edition, pages
Public Library of Science, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-163701 (URN)10.1371/journal.pone.0219259 (DOI)000482328300014 ()31287821 (PubMedID)
Available from: 2019-10-16 Created: 2019-10-16 Last updated: 2019-10-16Bibliographically approved
Aripaka, K., Gudey, S. K., Zang, G., Schmidt, A., Åhrling, S. S., Österman, L., . . . Landström, M. (2019). TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer. EBioMedicine, 45, 192-207
Open this publication in new window or tab >>TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
Show others...
2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed) Published
Abstract [en]

Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
beta-Catenin, LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161915 (URN)10.1016/j.ebiom.2019.06.046 (DOI)000475860000026 ()31262711 (PubMedID)2-s2.0-85067957867 (Scopus ID)
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved
Dongre, M., Singh, B., Aung, K. M., Larsson, P., Miftakhova, R. R., Persson, K., . . . Wai, S. N. (2018). Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts. Communications Biology, 1, Article ID 59.
Open this publication in new window or tab >>Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts
Show others...
2018 (English)In: Communications Biology, ISSN 2399-3642, Vol. 1, article id 59Article in journal (Refereed) Published
Abstract [en]

Using Caenorhabditis elegans as an infection host model for Vibrio cholerae predator interactions, we discovered a bacterial cytotoxin, MakA, whose function as a virulence factor relies on secretion via the flagellum channel in a proton motive force-dependent manner. The MakA protein is expressed from the polycistronic makDCBA (motility-associated killing factor) operon. Bacteria expressing makDCBA induced dramatic changes in intestinal morphology leading to a defecation defect, starvation and death in C. elegans. The Mak proteins also promoted V. cholerae colonization of the zebrafish gut causing lethal infection. A structural model of purified MakA at 1.9 Å resolution indicated similarities to members of a superfamily of bacterial toxins with unknown biological roles. Our findings reveal an unrecognized role for V. cholerae flagella in cytotoxin export that may contribute both to environmental spread of the bacteria by promoting survival and proliferation in encounters with predators, and to pathophysiological effects during infections.

Place, publisher, year, edition, pages
Springer Nature Publishing AG, 2018
National Category
Microbiology in the medical area
Research subject
Infectious Diseases; Molecular Biology
Identifiers
urn:nbn:se:umu:diva-155563 (URN)10.1038/s42003-018-0065-z (DOI)000461126500059 ()30271941 (PubMedID)
Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-04-04Bibliographically approved
Nord, H., Dennhag, N., Muck, J. & von Hofsten, J. (2016). Pax7 is required for establishment of the xanthophore lineage in zebrafish embryos. Molecular Biology of the Cell, 27(11), 1853-1862
Open this publication in new window or tab >>Pax7 is required for establishment of the xanthophore lineage in zebrafish embryos
2016 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 27, no 11, p. 1853-1862Article in journal (Refereed) Published
Abstract [en]

The pigment pattern of many animal species is a result of the arrangement of different types of pigment-producing chromatophores. The zebrafish has three different types of chromatophores: black melanophores, yellow xanthophores, and shimmering iridophores arranged in a characteristic pattern of golden and blue horizontal stripes. In the zebrafish embryo, chromatophores derive from the neural crest cells. Using pax7a and pax7b zebrafish mutants, we identified a previously unknown requirement for Pax7 in xanthophore lineage formation. The absence of Pax7 results in a severe reduction of xanthophore precursor cells and a complete depletion of differentiated xanthophores in embryos as well as in adult zebrafish. In contrast, the melanophore lineage is increased in pax7a/pax7b double-mutant embryos and larvae, whereas juvenile and adult pax7a/pax7b double-mutant zebrafish display a severe decrease in melanophores and a pigment pattern disorganization indicative of a xanthophore-deficient phenotype. In summary, we propose a novel role for Pax7 in the early specification of chromatophore precursor cells.

National Category
Cell Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-122559 (URN)10.1091/mbc.E15-12-0821 (DOI)000376777600015 ()27053658 (PubMedID)
Available from: 2016-06-22 Created: 2016-06-20 Last updated: 2018-06-07Bibliographically approved
Domellöf, F. P., Parkkonen, K., Lindström, M., Nord, H., von Hoffsten, J. & Li, Z. (2015). Desmin in extraocular muscles. Paper presented at Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 03-07, 2015, Denver, CO. Investigative Ophthalmology and Visual Science, 56(7)
Open this publication in new window or tab >>Desmin in extraocular muscles
Show others...
2015 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 56, no 7Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
ASSOC RESEARCH VISION OPHTHALMOLOGY, 2015
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-111515 (URN)000362882201317 ()
Conference
Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), MAY 03-07, 2015, Denver, CO
Available from: 2015-11-24 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Nord, H., Burguiere, A.-C., Muck, J., Nord, C., Ahlgren, U. & von Hofsten, J. (2014). Differential regulation of myosin heavy chains defines new muscle domains in zebrafish. Molecular Biology of the Cell, 25(8), 1384-1395
Open this publication in new window or tab >>Differential regulation of myosin heavy chains defines new muscle domains in zebrafish
Show others...
2014 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, no 8, p. 1384-1395Article in journal (Refereed) Published
Abstract [en]

Numerous muscle lineages are formed during myogenesis within both slow-and fast-specific cell groups. In this study, we show that six fast muscle-specific myosin heavy chain genes have unique expression patterns in the zebrafish embryo. The expression of tail-specific myosin heavy chain (fmyhc2.1) requires wnt signaling and is essential for fast muscle organization within the tail. Retinoic acid treatment results in reduced wnt signaling, which leads to loss of the fmyhc2.1 domain. Retinoic acid treatment also results in a shift of muscle identity within two trunk domains defined by expression of fmyhc1.2 and fmyhc1.3 in favor of the anteriormost myosin isoform, fmyhc1.2. In summary, we identify new muscle domains along the anteroposterior axis in the zebrafish that are defined by individual nonoverlapping, differentially regulated expression of myosin heavy chain isoforms.

Place, publisher, year, edition, pages
American Society for Cell Biology, 2014
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-92681 (URN)10.1091/mbc.E13-08-0486 (DOI)000339649400017 ()24523292 (PubMedID)
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2018-06-07Bibliographically approved
Kling, P., Modig, C., Mujahed, H., Khalaf, H., von Hofsten, J. & Olsson, P.-E. (2013). Differential regulation of the rainbow trout (Oncorhynchus mykiss) MT-A gene by nuclear factor interleukin-6 and activator protein-1. BMC Molecular Biology, 14(28)
Open this publication in new window or tab >>Differential regulation of the rainbow trout (Oncorhynchus mykiss) MT-A gene by nuclear factor interleukin-6 and activator protein-1
Show others...
2013 (English)In: BMC Molecular Biology, ISSN 1471-2199, E-ISSN 1471-2199, Vol. 14, no 28Article in journal (Refereed) Published
Abstract [en]

Background: Previously we have identified a distal region of the rainbow trout (Oncorhynchus mykiss) metallothionein-A (rtMT-A) enhancer region, being essential for free radical activation of the rtMT-A gene. The distal promoter region included four activator protein 1 (AP1) cis-acting elements and a single nuclear factor interleukin-6 (NF-IL6) element. In the present study we used the rainbow trout hepatoma (RTH-149) cell line to further examine the involvement of NF-IL6 and AP1 in rtMT-A gene expression following exposure to oxidative stress and tumour promotion.

Results: Using enhancer deletion studies we observed strong paraquat (PQ)-induced rtMT-A activation via NF-IL6 while the AP1 cis-elements showed a weak but significant activation. In contrast to mammals the metal responsive elements were not activated by oxidative stress. Electrophoretic mobility shift assay (EMSA) mutation analysis revealed that the two most proximal AP1 elements, AP1(1,2), exhibited strong binding to the AP1 consensus sequence, while the more distal AP1 elements, AP1(3,4) were ineffective. Phorbol-12-myristate-13-acetate (PMA), a known tumor promoter, resulted in a robust induction of rtMT-A via the AP1 elements alone. To determine the conservation of regulatory functions we transfected human Hep G2 cells with the rtMT-A enhancer constructs and were able to demonstrate that the cis-elements were functionally conserved. The importance of NF-IL6 in regulation of teleost MT is supported by the conservation of these elements in MT genes from different teleosts. In addition, PMA and PQ injection of rainbow trout resulted in increased hepatic rtMT-A mRNA levels.

Conclusions: These studies suggest that AP1 primarily is involved in PMA regulation of the rtMT-A gene while NF-IL6 is involved in free radical regulation. Taken together this study demonstrates the functionality of the NF-IL6 and AP-1 elements and suggests an involvement of MT in protection during pathological processes such as inflammation and cancer.

Keywords
Rainbow trout, Metallothionein-A promoter, Nuclear factor interleukin-6, Activator protein-1, Oxidative stress
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-85714 (URN)10.1186/1471-2199-14-28 (DOI)000329740300001 ()
Available from: 2014-02-14 Created: 2014-02-10 Last updated: 2018-06-08Bibliographically approved
Nord, H., Skalman, L. N. & von Hofsten, J. (2013). Six1 regulates proliferation of Pax7-positive muscle progenitors in zebrafish. Journal of Cell Science, 126(8), 1868-1880
Open this publication in new window or tab >>Six1 regulates proliferation of Pax7-positive muscle progenitors in zebrafish
2013 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 126, no 8, p. 1868-1880Article in journal (Refereed) Published
Abstract [en]

In the embryonic zebrafish, skeletal muscle fibres are formed from muscle progenitors in the paraxial mesoderm. The embryonic myotome is mostly constituted of fast-twitch-specific fibres, which are formed from a fast-specific progenitor cell pool. The most lateral fraction of the fast domain in the myotome of zebrafish embryos derives from the Pax7-positive dermomyotome-like cells. In this study, we show that two genes, belonging to the sine oculus class 1 (six1) genes (six1a and six1b), are both essential for the regulation of Pax7(+) cell proliferation and, consequently, in their differentiation during the establishment of the zebrafish dermomyotome. In both six1a and six1b morphant embryos, Pax7(+) cells are initially formed but fail to proliferate, as detected by reduced levels of the proliferation marker phosphohistone3 and reduced brdU incorporation. In congruence, overexpression of six1a or six1b leads to increased Pax7(+) cell number and reduced or alternatively delayed fibre cell differentiation. Bone morphogenetic protein signalling has previously been suggested to inhibit differentiation of Pax7(+) cells in the dermomyotome. Here we show that the remaining Pax7(+) cells in six1a and six1b morphant embryos also have significantly reduced pSmad1/5/8 levels and propose that this leads to a reduced proliferative activity, which may result in a premature differentiation of Pax7(+) cells in the zebrafish dermomyotome. In summary, we show a mechanism for Six1a and Six1b in establishing the Pax7(+) cell derived part of the fast muscle and suggest new important roles for Six1 in the regulation of the Pax7(+) muscle cell population through pSmad1/5/8 signalling.

Place, publisher, year, edition, pages
Cambridge, England: Company of Biologists Ltd, 2013
Keywords
Six1, Pax7, pSMAD 1/5/8, Dermomyotome, Myogenesis, Six1a, Six1b
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-73583 (URN)10.1242/jcs.119917 (DOI)000318975700015 ()
Available from: 2013-06-25 Created: 2013-06-25 Last updated: 2018-06-08Bibliographically approved
Maier, E., Nord, H., von Hofsten, J. & Gunhaga, L. (2011). A balance of BMP and notch activity regulates neurogenesis and olfactory nerve formation. PloS one, 6(2), e17379
Open this publication in new window or tab >>A balance of BMP and notch activity regulates neurogenesis and olfactory nerve formation
2011 (English)In: PloS one, ISSN 1932-6203, Vol. 6, no 2, p. e17379-Article in journal (Refereed) Published
Abstract [en]

Although the function of the adult olfactory system has been thoroughly studied, the molecular mechanisms regulating the initial formation of the olfactory nerve, the first cranial nerve, remain poorly defined. Here, we provide evidence that both modulated Notch and bone morphogenetic protein (BMP) signaling affect the generation of neurons in the olfactory epithelium and reduce the number of migratory neurons, so called epithelioid cells. We show that this reduction of epithelial and migratory neurons is followed by a subsequent failure or complete absence of olfactory nerve formation. These data provide new insights into the early generation of neurons in the olfactory epithelium and the initial formation of the olfactory nerve tract. Our results present a novel mechanism in which BMP signals negatively affect Notch activity in a dominant manner in the olfactory epithelium, thereby regulating neurogenesis and explain why a balance of BMP and Notch activity is critical for the generation of neurons and proper development of the olfactory nerve.

Identifiers
urn:nbn:se:umu:diva-42845 (URN)10.1371/journal.pone.0017379 (DOI)21383851 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
Organisations

Search in DiVA

Show all publications