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  • 1. Ai, Xingbin
    et al.
    Kitazawa, Toshio
    Do, Anh-Tri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kusche-Gullberg, Marion
    Labosky, Patricia A.
    Emerson, Charles P., Jr.
    SULF1 and SULF2 regulate heparan sulfate-mediated GDNF signaling for esophageal innervation2007In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 134, no 18, p. 3327-3338Article in journal (Refereed)
    Abstract [en]

    Heparan sulfate (HS) plays an essential role in extracellular signaling during development. Biochemical studies have established that HS binding to ligands and receptors is regulated by the fine 6-O-sulfated structure of HS; however, mechanisms that control sulfated HS structure and associated signaling functions in vivo are not known. Extracellular HS 6-O-endosulfatases, SULF1 and SULF2, are candidate enzymatic regulators of HS 6-O-sulfated structure and modulate HS-dependent signaling. To investigate Sulf regulation of developmental signaling, we have disrupted Sulf genes in mouse and identified redundant functions of Sulfs in GDNF-dependent neural innervation and enteric glial formation in the esophagus, resulting in esophageal contractile malfunction in Sulf1(-/ -); Sulf2(-/ -) mice. SULF1 is expressed in GDNF-expressing esophageal muscle and SULF2 in innervating neurons, establishing their direct functions in esophageal innervation. Biochemical and cell signaling studies show that Sulfs are the major regulators of HS 6-O-desulfation, acting to reduce GDNF binding to HS and to enhance GDNF signaling and neurite sprouting in the embryonic esophagus. The functional specificity of Sulfs in GDNF signaling during esophageal innervation was established by showing that the neurite sprouting is selectively dependent on GDNF, but not on neurotrophins or other signaling ligands. These findings provide the first in vivo evidence that Sulfs are essential developmental regulators of cellular HS 6-O-sulfation for matrix transmission and reception of GDNF signal from muscle to innervating neurons.

  • 2. Almeida, Alexandra D
    et al.
    Boije, Henrik
    Chow, Renee W
    He, Jie
    Tham, Jonathan
    Suzuki, Sachihiro C
    Harris, William A
    Spectrum of Fates: a new approach to the study of the developing zebrafish retina.2014In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 141, no 9, p. 1971-80Article in journal (Refereed)
    Abstract [en]

    The ability to image cells live and in situ as they proliferate and differentiate has proved to be an invaluable asset to biologists investigating developmental processes. Here, we describe a Spectrum of Fates approach that allows the identification of all the major neuronal subtypes in the zebrafish retina simultaneously. Spectrum of Fates is based on the combinatorial expression of differently coloured fluorescent proteins driven by the promoters of transcription factors that are expressed in overlapping subsets of retinal neurons. Here, we show how a Spectrum of Fates approach can be used to assess various aspects of neural development, such as developmental waves of differentiation, neuropil development, lineage tracing and hierarchies of fates in the developing zebrafish retina.

  • 3.
    Ando, Koji
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan.
    Wang, Weili
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld , Australia.
    Peng, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Chiba, Ayano
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka , Japan.
    Lagendijk, Anne K.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Barske, Lindsey
    Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem, Dept Stem Cell Biol & Regenerat Med, Keck Sch Med, Los Angeles, CA USA.
    Crump, J. Gage
    Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem, Dept Stem Cell Biol & Regenerat Med, Keck Sch Med, Los Angeles, CA USA.
    Stainier, Didier Y. R.
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, Bad Nauheim, Germany.
    Lendahl, Urban
    Karolinska Inst, Dept Cell & Mol Biol, Biomedicum, Stockholm, Sweden; Karolinska Inst, Dept Med, ICMC, Huddinge, Sweden.
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Hogan, Benjamin M.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Fukuhara, Shigetomo
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan; Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Musashi Kosugi Hosp, Kawasaki, Kanagawa, Japan.
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan; Natl Cerebral & Cardiovasc Ctr, AMED CREST, Dept Cell Biol, Suita, Osaka, Japan.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med, ICMC, Huddinge, Sweden.
    Peri-arterial specification of vascular mural cells from naive mesenchyme requires Notch signaling2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 2, article id UNSP dev165589Article in journal (Refereed)
    Abstract [en]

    Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naive pdgfrb(low) mesenchymal cells. The emergence of peri-arterial pdgfrb(high) MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrb(high) MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrb(high) MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.

  • 4. Anjard, Christophe
    et al.
    Söderbom, Fredrik
    Dept. of Microbiology, Swedish University of Agricultural Sciences Box 7025, 750 07 Uppsala, Sweden .
    Loomis, William F
    Requirements for the adenylyl cyclases in the development of Dictyostelium2001In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 128, no 18, p. 3649-3654Article in journal (Refereed)
    Abstract [en]

    It has been suggested that all intracellular signaling by cAMP during development of Dictyostelium is mediated by the cAMP-dependent protein kinase, PKA, since cells carrying null mutations in the acaA gene that encodes adenylyl cyclase can develop so as to form fruiting bodies under some conditions if PKA is made constitutive by overexpressing the catalytic subunit. However, a second adenylyl cyclase encoded by acrA has recently been found that functions in a cell autonomous fashion during late development. We have found that expression of a modified acaA gene rescues acrA- mutant cells indicating that the only role played by ACR is to produce cAMP. To determine whether cells lacking both adenylyl cyclase genes can develop when PKA is constitutive we disrupted acrA in a acaA- PKA-C(over) strain. When developed at high cell densities, acrA- acaA- PKA-C(over) cells form mounds, express cell type-specific genes at reduced levels and secrete cellulose coats but do not form fruiting bodies or significant numbers of viable spores. Thus, it appears that synthesis of cAMP is required for spore differentiation in Dictyostelium even if PKA activity is high.

  • 5.
    Chaudhury, Smrita
    et al.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia..
    Okuda, Kazuhide S.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia.;Peter MacCallum Canc Ctr, Organogenesis & Canc Program, Melbourne, Vic 3000, Australia..
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia..
    Lagendijk, Anne K.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia..
    Paterson, Scott
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia.;Peter MacCallum Canc Ctr, Organogenesis & Canc Program, Melbourne, Vic 3000, Australia..
    Baillie, Gregory J.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia..
    Simons, Cas
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia.;Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia..
    Smith, Kelly A.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia.;Univ Melbourne, Dept Physiol, Parkville, Vic 3010, Australia..
    Hogan, Benjamin M.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia.;Peter MacCallum Canc Ctr, Organogenesis & Canc Program, Melbourne, Vic 3000, Australia.;Univ Melbourne, Dept Anat & Neurosci, Parkville, Vic 3010, Australia..
    Bower, Neil, I
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, St Lucia, Qld 4072, Australia..
    Localised Collagen2a1 secretion supports lymphatic endothelial cell migration in the zebrafish embryo2020In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 147, no 18, article id dev190983Article in journal (Refereed)
    Abstract [en]

    The lymphatic vasculature develops primarily from pre-existing veins. A pool of lymphatic endothelial cells (LECs) first sprouts from cardinal veins followed by migration and proliferation to colonise embryonic tissues. Although much is known about the molecular regulation of LEC fate and sprouting during early lymphangiogenesis, we know far less about the instructive and permissive signals that support LEC migration through the embryo. Using a forward genetic screen, we identified mbtps1 and sec23a, components of the COP-II protein secretory pathway, as essential for developmental lymphangiogenesis. In both mutants, LECs initially depart the cardinal vein but then fail in their ongoing migration. A key cargo that failed to be secreted in both mutants was a type II collagen (Col2a1). Col2a1 is normally secreted by notochord sheath cells, alongside which LECs migrate. col2a1a mutants displayed defects in the migratory behaviour of LECs and failed lymphangiogenesis. These studies thus identify Col2a1 as a key cargo secreted by notochord sheath cells and required for the migration of LECs. These findings combine with our current understanding to suggest that successive cell-to-cell and cell-matrix interactions regulate the migration of LECs through the embryonic environment during development.

  • 6.
    Chiang, Ivy Kim-Ni
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Fritzsche, Martin
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Pichol-Thievend, Cathy
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Neal, Alice
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Holmes, Kelly
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Lagendijk, Anne
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Overman, Jeroen
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    D'Angelo, Donatella
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Omini, Alice
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Hermkens, Dorien
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Lesieur, Emmanuelle
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Liu, Ke
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Ratnayaka, Indrika
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Corada, Monica
    FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy..
    Bou-Gharios, George
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Carroll, Jason
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy.
    Schulte-Merker, Stefan
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Hogan, Benjamin
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Beltrame, Monica
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    De Val, Sarah
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Francois, Mathias
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development2017In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 14, p. 2629-2639Article in journal (Refereed)
    Abstract [en]

    Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancerswere able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo. Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

  • 7.
    Christian, Jan L.
    et al.
    Univ Utah, Sch Med, Div Hematol & Hematol Malignancies, Dept Neurobiol & Anat & Internal Med, Salt Lake City.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The TGFβ superfamily in Lisbon: navigating through development and disease2017In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 24, p. 4476-4480Article in journal (Other academic)
    Abstract [en]

    The 10th FASEB meeting ‘The TGFβ Superfamily: Signaling in Development and Disease' took place in Lisbon, Portugal, in July 2017. As we review here, the findings presented at the meeting highlighted the important contributions of TGFβ family signaling to normal development, adult homeostasis and disease, and also revealed novel mechanisms by which TGFβ signals are transduced.

  • 8.
    Cottarelli, Azzurra
    et al.
    FIRC Inst Mol Oncol Fdn IFOM, I-20139 Milan, Italy.;Columbia Univ, Dept Neurol, Irving Med Ctr, New York, NY 10032 USA..
    Corada, Monica
    FIRC Inst Mol Oncol Fdn IFOM, I-20139 Milan, Italy..
    Beznoussenko, Galina, V
    FIRC Inst Mol Oncol Fdn IFOM, I-20139 Milan, Italy..
    Mironov, Alexander A.
    FIRC Inst Mol Oncol Fdn IFOM, I-20139 Milan, Italy..
    Globisch, Maria A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Biswas, Saptarshi
    Columbia Univ, Dept Neurol, Irving Med Ctr, New York, NY 10032 USA..
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Agalliu, Dritan
    Columbia Univ, Dept Neurol, Irving Med Ctr, New York, NY 10032 USA.;Columbia Univ, Dept Pathol & Cell Biol, Irving Med Ctr, New York, NY 10032 USA..
    Lampugnani, Maria Grazia
    FIRC Inst Mol Oncol Fdn IFOM, I-20139 Milan, Italy.;Ist Ric Farmacolog Mario Negri, I-20156 Milan, Italy..
    Dejana, Elisabetta
    FIRC Inst Mol Oncol Fdn IFOM, I-20139 Milan, Italy.;Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75237 Uppsala, Sweden.;Univ Milan, Sch Med, Dept Oncol & Haematooncol, I-20122 Milan, Italy..
    Fgfbp1 promotes blood-brain barrier development by regulating collagen IV deposition and maintaining Wnt/beta-catenin signaling2020In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 147, no 16, article id dev185140Article in journal (Refereed)
    Abstract [en]

    Central nervous system (CNS) blood vessels contain a functional blood-brain barrier (BBB) that is necessary for neuronal survival and activity. Although Wnt/beta-catenin signaling is essential for BBB development, its downstream targets within the neurovasculature remain poorly understood. To identify targets of Wnt/beta-catenin signaling underlying BBB maturation, we performed a microarray analysis that identified Fgfbp1 as a novel Wnt/beta-catenin-regulated gene in mouse brain endothelial cells (mBECs). Fgfbp1 is expressed in the CNS endothelium and secreted into the vascular basement membrane during BBB formation. Endothelial genetic ablation of Fgfbp1 results in transient hypervascularization but delays BBB maturation in specific CNSregions, as evidenced by both upregulation of Plvap and increased tracer leakage across the neurovasculature due to reduced Wnt/beta-catenin activity. In addition, collagen IV deposition in the vascular basement membrane is reduced in mutant mice, leading to defective endothelial cell-pericyte interactions. Fgfbp1 is required cell-autonomously in mBECs to concentrate Wnt ligands near cell junctions and promote maturation of their barrier properties in vitro. Thus, Fgfbp1 is a crucial extracellular matrix protein during BBB maturation that regulates cell-cell interactions and Wnt/beta-catenin activity.

  • 9.
    de Oliveira, Marta Bastos
    et al.
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany..
    Meier, Katja
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany..
    Jung, Simone
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany..
    Bartels-Klein, Eireen
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany..
    Coxam, Baptiste
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany..
    Geudens, Ilse
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ, Dept Immunol Genet & Pathol, S-75237 Uppsala, Sweden.;VIB, Vasc Patterning Lab, Ctr Canc Biol, B-3000 Leuven, Belgium..
    Szymborska, Anna
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany..
    Skoczylas, Renae
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fechner, Ines
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany..
    Koltowska, Katarzyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gerhardt, Holger
    Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, Potsdamer Str 58, D-10785 Berlin, Germany.;VIB, Vasc Patterning Lab, Ctr Canc Biol, B-3000 Leuven, Belgium.;Katholieke Univ Leuven, Dept Oncol, Vasc Patterning Lab, Ctr Canc Biol, B-3000 Leuven, Belgium.;Berlin Inst Hlth BIH, Anna Louisa Karsch Str 2, D-10178 Berlin, Germany..
    Vasohibin 1 selectively regulates secondary sprouting and lymphangiogenesis in the zebrafish trunk2021In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 148, no 4, article id dev194993Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that Vasohibin 1 (Vash1) is stimulated by VEGFs in endothelial cells and that its overexpression interferes with angiogenesis in vivo. Recently, Vash1 was found to mediate tubulin detyrosination, a post-translational modification that is implicated in many cell functions, such as cell division. Here, we used the zebrafish embryo to investigate the cellular and subcellular mechanisms of Vash1 on endothelial microtubules during formation of the trunk vasculature. We show that microtubules within venous-derived secondary sprouts are strongly and selectively detyrosinated in comparison with other endothelial cells, and that this difference is lost upon vash1 knockdown. Vash1 depletion in zebrafish specifically affected secondary sprouting from the posterior cardinal vein, increasing endothelial cell divisions and cell number in the sprouts. We show that altering secondary sprout numbers and structure upon Vash1 depletion leads to defective lymphatic vessel formation and ectopic lymphatic progenitor specification in the zebrafish trunk.

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  • 10. Dufour, Audrey
    et al.
    Egea, Joaquim
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Klein, Rüdiger
    Vanderhaeghen, Pierre
    Genetic analysis of EphA-dependent signaling mechanisms controlling topographic mapping in vivo2006In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 133, no 22, p. 4415-4420Article in journal (Refereed)
    Abstract [en]

    Ephrin/Eph ligands and receptors are best known for their prominent role in topographic mapping of neural connectivity. Despite the large amount of work centered on ephrin/Eph-dependent signaling pathways in various cellular contexts, the molecular mechanisms of action of Eph receptors in neural mapping, requiring dynamic interactions between complementary gradients of ephrins and Eph receptors, remain largely unknown. Here, we investigated in vivo the signaling mechanisms of neural mapping mediated by the EphA4 receptor, previously shown to control topographic specificity of thalamocortical axons in the mouse somatosensory system. Using axon tracing analyses of knock-in mouse lines displaying selective mutations for the Epha4 gene, we determined for the first time which intracellular domains of an Eph receptor are required for topographic mapping. We provide direct in vivo evidence that the tyrosine kinase domain of EphA4, as well as a tight regulation of its activity, are required for topographic mapping of thalamocortical axons, whereas non-catalytic functional modules, such as the PDZ-binding motif (PBM) and the Sterile-alpha motif (SAM) domain, are dispensable. These data provide a novel insight into the molecular mechanisms of topographic mapping, and constitute a physiological framework for the dissection of the downstream signaling cascades involved.

  • 11.
    Eklund, D. Magnus
    et al.
    University of Agricultural Sciences, Uppsala, Sweden..
    Thelander, Mattias
    University of Agricultural Sciences, Uppsala, Sweden..
    Landberg, Katarina
    University of Agricultural Sciences, Uppsala, Sweden..
    Ståldal, Veronika
    University of Agricultural Sciences, Uppsala, Sweden..
    Nilsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. University of Agricultural Sciences, Uppsala, Sweden..
    Valsecchi, Isabel
    University of Agricultural Sciences, Uppsala, Sweden..
    Pederson, Eric R. A.
    University of Agricultural Sciences, Uppsala, Sweden..
    Kowalczyk, Mariusz
    Swedish University of Agricultural Sciences, Umeå, Sweden..
    Ljung, Karin
    Swedish University of Agricultural Sciences, Umeå, Sweden..
    Ronne, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundberg, Eva
    University of Agricultural Sciences, Uppsala, Sweden..
    Homologues of the Arabidopsis thaliana SHI/STY/LRP1 genes control auxin biosynthesis and affect growth and development in the moss Physcomitrella patens2010In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 137, no 8, p. 1275-1284Article in journal (Refereed)
    Abstract [en]

    The plant hormone auxin plays fundamental roles in vascular plants. Although exogenous auxin also stimulates developmental transitions and growth in non-vascular plants, the effects of manipulating endogenous auxin levels have thus far not been reported. Here, we have altered the levels and sites of auxin production and accumulation in the moss Physcomitrella patens by changing the expression level of homologues of the Arabidopsis SHI/STY family proteins, which are positive regulators of auxin biosynthesis genes. Constitutive expression of PpSHI1 resulted in elevated auxin levels, increased and ectopic expression of the auxin response reporter GmGH3pro:GUS, and in an increased caulonema/chloronema ratio, an effect also induced by exogenous auxin application. In addition, we observed premature ageing and necrosis in cells ectopically expressing PpSHI1. Knockout of either of the two PpSHI genes resulted in reduced auxin levels and auxin biosynthesis rates in leafy shoots, reduced internode elongation, delayed ageing, a decreased caulonema/chloronema ratio and an increased number of axillary hairs, which constitute potential auxin biosynthesis sites. Some of the identified auxin functions appear to be analogous in vascular and non-vascular plants. Furthermore, the spatiotemporal expression of the PpSHI genes and GmGH3pro:GUS strongly overlap, suggesting that local auxin biosynthesis is important for the regulation of auxin peak formation in non-vascular plants.

  • 12.
    Gouveia, Leonor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGF-A signaling is required for secondary alveolar septation and controls epithelial proliferation in the developing lung2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 7, article id dev161976Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor A (PDGF-A) signaling through PDGF receptor a is essential for alveogenesis. Previous studies have shown that Pdgfa(-/-) mouse lungs have enlarged alveolar airspace with absence of secondary septation, both distinctive features of bronchopulmonary dysplasia. To study how PDGF-A signaling is involved in alveogenesis, we generated lung-specific Pdgfa knockout mice (Pdgfa(fl/-); Spc-cre) and characterized their phenotype postnatally. Histological differences between mutant mice and littermate controls were visible after the onset of alveogenesis and maintained until adulthood. Additionally, we generated Pdgfa(fl/-); Spc-cre; Pdgfra(GFP/+) mice in which Pdgfra(+) cells exhibit nuclear GFP expression. In the absence of PDGF-A, the number of Pdgfra(GFP+) cells was significantly decreased. In addition, proliferation of Pdgfra(GFP+) cells was reduced. During alveogenesis, Pdgfra(GFP+) myofibroblasts failed to form the alpha-smooth muscle actin rings necessary for alveolar secondary septation. These results indicate that PDGF-A signaling is involved in myofibroblast proliferation and migration. In addition, we show an increase in both the number and proliferation of alveolar type II cells in Pdgfa(fl/-); Spc-cre lungs, suggesting that the increased alveolar airspace is not caused solely by deficient myofibroblast function.

  • 13. Hallböök, F
    et al.
    Ayer-Lelièvre, C
    Ebendal, T
    Persson, H
    Expression of nerve growth factor receptor mRNA during early development of the chicken embryo: emphasis on cranial ganglia.1990In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 108, no 4, p. 693-704Article in journal (Refereed)
    Abstract [en]

    In situ hybridization with beta-nerve growth factor receptor (NGF-R) oligonucleotide probes was used to study NGF-R mRNA expression in early chicken embryos. Sections through the region of the visceral arches showed high levels of NGF-R mRNA in mesenchyme of the visceral arches, neural tube and myotomes. Labelling was also seen over E3 primordium of the trigeminal ganglion (V) and in the placodal thickening of the petrosal (IX) and nodose (X) ganglionic primordia. In the E5 embryo, all cranial sensory ganglia (V, VII, VIII, IX, X) expressed NGF-R mRNA although at varying levels with higher levels in the ganglia of the Vth, IXth and Xth cranial nerves than in ganglia of the VIIth and the VIIIth nerves. Within ganglia of the Vth, IXth and Xth cranial nerves, levels of NGF-R mRNA were higher in regions containing placode-derived neurons, than in regions with neural-crest-derived neurons. The placode-derived nodose ganglion (X) expressed NGF-R mRNA at all stages of development. In the E15 embryo and later in development, two thirds of the large neuron-like cells expressed high levels of NGF-R mRNA. Our results show that expression of NGF-R mRNA, in peripheral neurons, is not restricted to cells of neural crest origin. We also show a transient expression of NGF-R mRNA early in development in a wide range of non-neuronal differentiating cells. The high level of NGF-R mRNA in early differentiating tissues suggest that the NGF-R plays a wider role during development than previously anticipated.

  • 14. Helker, Christian S M
    et al.
    Mullapudi, Sri-Teja
    Mueller, Laura M
    Preussner, Jens
    Tunaru, Sorin
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kwon, Hyouk-Bum
    Kreuder, Florian
    Lancman, Joseph J
    Bonnavion, Remy
    Dong, P Duc Si
    Looso, Mario
    Offermanns, Stefan
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Spagnoli, Francesca M
    Stainier, Didier Y R
    A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 14, article id dev172569Article in journal (Refereed)
    Abstract [en]

    An early step in pancreas development is marked by the expression of the transcription factor Pdx1 within the pancreatic endoderm, where it is required for the specification of all endocrine cell types. Subsequently, Pdx1 expression becomes restricted to the β-cell lineage, where it plays a central role in β-cell function. This pivotal role of Pdx1 at various stages of pancreas development makes it an attractive target to enhance pancreatic β-cell differentiation and increase β-cell function. In this study, we used a newly generated zebrafish reporter to screen over 8000 small molecules for modulators of pdx1 expression. We found four hit compounds and validated their efficacy at different stages of pancreas development. Notably, valproic acid treatment increased pancreatic endoderm formation, while inhibition of TGFβ signaling led to α-cell to β-cell transdifferentiation. HC toxin, another HDAC inhibitor, enhances β-cell function in primary mouse and human islets. Thus, using a whole organism screening strategy, this study identified new pdx1 expression modulators that can be used to influence different steps in pancreas and β-cell development.

  • 15.
    Karlsson, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Mayordomo, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Reichardt, Louis
    Catsicas, Stefan
    Karten, Harvey
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Nerve growth factor is expressed by postmitotic avian retinal horizontal cells and supports their survival during development in an autocrine mode of action2001In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 128, no 4, p. 471-479Article in journal (Refereed)
    Abstract [en]

    Cell death in the developing retina is regulated, but so far little is known about what factors regulate the cell death. Several neurotrophic factors and receptors, including the neurotrophins and Trk receptors, are expressed during the critical time. We have studied the developing avian retina with respect to the role of nerve growth factor (NGF) in these processes. Our starting point for the work was that NGF and its receptor TrkA are expressed in a partially overlapping pattern in the inner nuclear layer of the developing retina. Our results show that TrkA and NGF-expressing cells are postmitotic. The first NGF-expressing cells were found on the vitreal side of the central region of E5.5-E6 retina. This pattern changed and NGF-expressing cells identified as horizontal cells were later confined to the external inner nuclear layer. We show that these horizontal cells co-express TrkA and NGF, unlike a subpopulation of amacrine cells that only expresses TrkA. In contrast to the horizontal cells, which survive, the majority of the TrkA-expressing amacrine cells die during a period of cell death in the inner nuclear layer. Intraocular injections of NGF protein rescued the dying amacrine cells and injection of antisense oligonucleotides for NGF that block its synthesis, caused death among the TrkA-expressing horizontal cells, which normally would survive. Our results suggest that NGF supports the survival of TrkA expressing avian horizontal cells in an autocrine mode of action in the retina of E10-E12 chicks. The cells co-express TrkA and NGF and the role for NGF is to maintain the TrkA-expressing horizontal cells. The TrkA-expressing amacrine cells are not supported by NGF and subsequently die. In addition to the effect on survival, our results suggest that NGF plays a role in horizontal cell plasticity.

  • 16.
    Laviña, Bàrbara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Castro, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Cruys, Bert
    VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Leuven, Belgium; Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Álvarez-Aznar, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Carmeliet, Peter
    VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Leuven, Belgium; Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Leuven, Belgium.
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Computat Biol Lab, Boston, MA USA.
    Brakebusch, Cord
    Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Huddinge, ICMC, Stockholm, Sweden.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 13, article id UNSP dev161182Article in journal (Refereed)
    Abstract [en]

    Formation and homeostasis of the vascular system requires several coordinated cellular functions, but their precise interplay during development and their relative importance for vascular pathologies remain poorly understood. Here, we investigated the endothelial functions regulated by Cdc42 and their in vivo relevance during angiogenic sprouting and vascular morphogenesis in the postnatal mouse retina. We found that Cdc42 is required for endothelial tip cell selection, directed cell migration and filopodia formation, but dispensable for cell proliferation or apoptosis. Although the loss of Cdc42 seems generally compatible with apical-basal polarization and lumen formation in retinal blood vessels, it leads to defective endothelial axial polarization and to the formation of severe vascular malformations in capillaries and veins. Tracking of Cdc42-depleted endothelial cells in mosaic retinas suggests that these capillary-venous malformations arise as a consequence of defective cell migration, when endothelial cells that proliferate at normal rates are unable to re-distribute within the vascular network.

  • 17.
    Mohammad, Faizaan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mondal, Tanmoy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Guseva, Natalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pandey, Gaurav Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kanduri, Chandrasekhar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt12010In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 137, no 15, p. 2493-2499Article in journal (Refereed)
    Abstract [en]

    A long noncoding RNA, Kcnq1ot1, regulates the expression of both ubiquitously and tissue-specific imprinted genes within the Kcnq1 domain. However, the functional sequences of the Kcnq1ot1 RNA that mediate lineage-specific imprinting are unknown. Here, we have generated a knockout mouse with a deletion encompassing an 890-bp silencing domain (Delta890) downstream of the Kcnq1ot1 promoter. Maternal transmission of the Delta890 allele has no effect on imprinting, whereas paternal inheritance of the deletion leads to selective relaxation of the imprinting of ubiquitously imprinted genes to a variable extent in a tissue-specific manner. Interestingly, the deletion affects DNA methylation at somatically acquired differentially methylated regions (DMRs), but does not affect the histone modifications of the ubiquitously imprinted genes. Importantly, we found that Kcnq1ot1 recruits Dnmt1 to somatic DMRs by interacting with Dnmt1, and that this interaction was significantly reduced in the Delta890 mice. Thus, the ubiquitous and placental-specific imprinting of genes within the Kcnq1 domain might be mediated by distinct mechanisms, and Kcnq1ot1 RNA might mediate the silencing of ubiquitously imprinted genes by maintaining allele-specific methylation through its interactions with Dnmt1.

  • 18.
    Mohammad, Faizaan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandey, Gaurav Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mondal, Tanmoy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Redrup, Lisa
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kanduri, Chandrasekhar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing2012In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 139, no 15, p. 2792-2803Article in journal (Refereed)
    Abstract [en]

    Establishment of silencing by noncoding RNAs (ncRNAs) via targeting of chromatin remodelers is relatively well investigated; however, their role in the maintenance of silencing is poorly understood. Here, we explored the functional role of the long ncRNA Kcnq1ot1 in the maintenance of transcriptional gene silencing in the one mega-base Kcnq1 imprinted domain in a transgenic mouse model. By conditionally deleting the Kcnq1ot1 ncRNA at different stages of mouse development, we suggest that Kcnq1ot1 ncRNA is required for the maintenance of the silencing of ubiquitously imprinted genes (UIGs) at all developmental stages. In addition, Kcnq1ot1 ncRNA is also involved in guiding and maintaining the CpG methylation at somatic differentially methylated regions flanking the UIGs, which is a hitherto unknown role for a long ncRNA. On the other hand, silencing of some of the placental-specific imprinted genes (PIGs) is maintained independently of Kcnq1ot1 ncRNA. Interestingly, the non-imprinted genes (NIGs) that escape RNA-mediated silencing are enriched with enhancer-specific modifications. Taken together, this study illustrates the gene-specific maintenance mechanisms operational at the Kcnq1 locus for tissue-specific transcriptional gene silencing and activation.

  • 19.
    Moustakas, Aristidis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    The regulation of TGFβ signal transduction2009In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 136, no 22, p. 3699-3714Article, review/survey (Refereed)
    Abstract [en]

    Transforming growth factor beta (TGFbeta) pathways are implicated in metazoan development, adult homeostasis and disease. TGFbeta ligands signal via receptor serine/threonine kinases that phosphorylate, and activate, intracellular Smad effectors as well as other signaling proteins. Oligomeric Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGFbeta family members. Signaling is modulated by negative-feedback regulation via inhibitory Smads. We review here the mechanisms of TGFbeta signal transduction in metazoans and emphasize events crucial for embryonic development.

  • 20. Passante, Lara
    et al.
    Gaspard, Nicolas
    Degraeve, Mélanie
    Frisén, Jonas
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    De Maertelaer, Viviane
    Vanderhaeghen, Pierre
    Temporal regulation of ephrin/Eph signalling is required for the spatial patterning of the mammalian striatum2008In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 135, no 19, p. 3281-3290Article in journal (Refereed)
    Abstract [en]

    Brain structures, whether mature or developing, display a wide diversity of pattern and shape, such as layers, nuclei or segments. The striatum in the mammalian forebrain displays a unique mosaic organization (subdivided into two morphologically and functionally defined neuronal compartments: the matrix and the striosomes) that underlies important functional features of the basal ganglia. Matrix and striosome neurons are generated sequentially during embryonic development, and segregate from each other to form a mosaic of distinct compartments. However, the molecular mechanisms that underlie this time-dependent process of neuronal segregation remain largely unknown. Using a novel organotypic assay, we identified ephrin/Eph family members as guidance cues that regulate matrix/striosome compartmentalization. We found that EphA4 and its ephrin ligands displayed specific temporal patterns of expression and function that play a significant role in the spatial segregation of matrix and striosome neurons. Analysis of the striatal patterning in ephrin A5/EphA4 mutant mice further revealed the requirement of EphA4 signalling for the proper sorting of matrix and striosome neuronal populations in vivo. These data constitute the first identification of genes involved in striatal compartmentalization, and reveal a novel mechanism by which the temporal control of guidance cues enables neuronal segregation, and thereby the generation of complex cellular patterns in the brain.

  • 21.
    Ramachandran, Prashanth
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany. Linnean Ctr Plant Biol, Ullsv 24E, SE-75651 Uppsala, Sweden.
    Wang, Guodong
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany. Linnean Ctr Plant Biol, Ullsv 24E, SE-75651 Uppsala, Sweden.
    Augstein, Frauke
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany. Linnean Ctr Plant Biol, Ullsv 24E, SE-75651 Uppsala, Sweden.
    de Vries, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany. Linnean Ctr Plant Biol, Ullsv 24E, SE-75651 Uppsala, Sweden, Canada..
    Carlsbecker, Annelie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany. Linnean Ctr Plant Biol, Ullsv 24E, SE-75651 Uppsala, Sweden.
    Continuous root xylem formation and vascular acclimation to water deficit involves endodermal ABA signalling via miR1652018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 3, article id dev159202Article in journal (Refereed)
    Abstract [en]

    The plant root xylem comprises a specialized tissue for water distribution to the shoot. Despite its importance, its potential morphological plasticity in response to environmental conditions such as limited water availability has not been thoroughly studied. Here, we identify a role for the phytohormone abscisic acid (ABA) for proper xylem development and describe how ABA signalling-mediated effects on core developmental regulators are employed to alter xylem morphology under limited water availability in Arabidopsis. Plants with impaired ABA biosynthesis and reduced ABA signalling in the cell layer surrounding the vasculature displayed defects in xylem continuity, suggesting that non-cell autonomous ABA signalling is required for proper xylem development. Conversely, upon external ABA application or under limited water availability, extra xylem strands were formed. The observed xylem developmental alterations were dependent on adequate endodermal ABA signalling, which activated MIR165A. This resulted in increased miR165 levels that repress class III HD-ZIP transcription factors in the stele. We conclude that a pathway known to control core developmental features is employed as a means of modifying plant xylem morphology under conditions of environmental stress.

  • 22.
    Schimmel, Lilian
    et al.
    Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072 , Australia..
    Fukuhara, Daisuke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Richards, Mark
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jin, Yi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Essebier, Patricia
    Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072 , Australia..
    Frampton, Emmanuelle
    Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072 , Australia..
    Hedlund, Marie
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dejana, Elisabetta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gordon, Emma
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
    c-Src controls stability of sprouting blood vessels in the developing retina independently of cell-cell adhesion through focal adhesion assembly2020In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 147, no 7, article id dev185405Article in journal (Refereed)
    Abstract [en]

    Endothelial cell adhesion is implicated in blood vessel sprout formation, yet how adhesion controls angiogenesis, and whether it occurs via rapid remodeling of adherens junctions or focal adhesion assembly, or both, remains poorly understood. Furthermore, how endothelial cell adhesion is controlled in particular tissues and under different conditions remains unexplored. Here, we have identified an unexpected role for spatiotemporal c-Src activity in sprouting angiogenesis in the retina, which is in contrast to the dominant focus on the role of c-Src in the maintenance of vascular integrity. Thus, mice specifically deficient in endothelial c-Src displayed significantly reduced blood vessel sprouting and loss in actin-rich filopodial protrusions at the vascular front of the developing retina. In contrast to what has been observed during vascular leakage, endothelial cell-cell adhesion was unaffected by loss of c-Src. Instead, decreased angiogenic sprouting was due to loss of focal adhesion assembly and cell-matrix adhesion, resulting in loss of sprout stability. These results demonstrate that c-Src signaling at specified endothelial cell membrane compartments (adherens junctions or focal adhesions) control vascular processes in a tissue- and context-dependent manner.

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  • 23. Svensson, Kristian
    et al.
    Mattsson, R
    Tharappel, JC
    Wentzel, Parri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pilartz, M
    MacLaughlin, J
    Miller, SJ
    Olsson, T
    Eriksson, Ulf J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ohlsson, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. zoologisk utvecklingsbiologi. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
    The paternal allele of the H19 gene is silenced in a stepwise manner duringearly mouse development: the acetylation status of histones mya be involved in the generation of variegated expression patter1998In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 125, no 1, p. 61-69Article in journal (Refereed)
    Abstract [en]

    Transcriptional silencing can reflect heritable, epigenetic inactivation of genes, either singly or in groups, during the life-time of an organism. This phenomenon is exemplified by parent-of-origin-specific inactivation events (genomic imprinting) for a subset of mammalian autosomal genes, such as H19. Very little is known, however, about the timing and mechanism(s) of silencing of the paternal H19 allele during mouse development. Using a novel in situ approach, we present evidence that the silencing of the paternal H19 allele is progressive in the trophectodermal lineage during early mouse development and generates variegated expression patterns. The silencing process apparently involves recruitment of histone deacetylases since the mosaic paternal-specific H19 expression reappears in trichostatin A-treated mouse conceptuses, undergoing in vitro organogenesis. Moreover, the paternal H19 alleles of PatDup.d7 placentas, in which a region encompassing the H19 locus of chromosome 7 is bipaternally derived, partially escape the silencing process and are expressed in a variegated manner. We suggest that allele-specific silencing of H19 share some common features with chromatin-mediated silencing in position-effect variegation.

  • 24.
    Söderbom, Fredrik
    et al.
    Center for Molecular Genetics, Department of Biology, University of California San Diego, La Jolla, CA 92093, USA.
    Anjard, C
    Iranfar, N
    Fuller, D
    Loomis, W F
    An adenylyl cyclase that functions during late development of Dictyostelium1999In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 126, no 23, p. 5463-5471Article in journal (Refereed)
    Abstract [en]

    A variety of extracellular signals lead to the accumulation of cAMP which can act as a second message within cells by activating protein kinase A (PKA). Expression of many of the essential developmental genes in Dictyostelium discoideum are known to depend on PKA activity. Cells in which the receptor-coupled adenylyl cyclase gene, acaA, is genetically inactivated grow well but are unable to develop. Surprisingly, acaA(-) mutant cells can be rescued by developing them in mixtures with wild-type cells, suggesting that another adenylyl cyclase is present in developing cells that can provide the internal cAMP necessary to activate PKA. However, the only other known adenylyl cyclase gene in Dictyostelium, acgA, is only expressed during germination of spores and plays no role in the formation of fruiting bodies. By screening morphological mutants generated by Restriction Enzyme Mediated Integration (REMI) we discovered a novel adenylyl cyclase gene, acrA, that is expressed at low levels in growing cells and at more than 25-fold higher levels during development. Growth and development up to the slug stage are unaffected in acrA(-) mutant strains but the cells make almost no viable spores and produce unnaturally long stalks. Adenylyl cyclase activity increases during aggregation, plateaus during the slug stage and then increases considerably during terminal differentiation. The increase in activity following aggregation fails to occur in acrA(-) cells. As long as ACA is fully active, ACR is not required until culmination but then plays a critical role in sporulation and construction of the stalk.

  • 25. Ursache, Robertas
    et al.
    Miyashima, Shunsuke
    Chen, Qingguo
    Vaten, Anne
    Nakajima, Keiji
    Carlsbecker, Annelie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Physiological Botany.
    Zhao, Yunde
    Helariutta, Yka
    Dettmer, Jan
    Tryptophan-dependent auxin biosynthesis is required for HD-ZIP III-mediated xylem patterning2014In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 141, no 6, p. 1250-1260Article in journal (Refereed)
    Abstract [en]

    The development and growth of higher plants is highly dependent on the conduction of water and minerals throughout the plant by xylem vessels. In Arabidopsis roots the xylem is organized as an axis of cell files with two distinct cell fates: the central metaxylem and the peripheral protoxylem. During vascular development, high and low expression levels of the class III HD-ZIP transcription factors promote metaxylem and protoxylem identities, respectively. Protoxylem specification is determined by both mobile, ground tissue-emanating miRNA165/6 species, which downregulate, and auxin concentrated by polar transport, which promotes HD-ZIP III expression. However, the factors promoting high HD-ZIP III expression for metaxylem identity have remained elusive. We show here that auxin biosynthesis promotes HD-ZIP III expression and metaxylem specification. Several auxin biosynthesis genes are expressed in the outer layers surrounding the vascular tissue in Arabidopsis root and downregulation of HD-ZIP III expression accompanied by specific defects in metaxylem development is seen in auxin biosynthesis mutants, such as trp2-12, wei8 tar2 or a quintuple yucca mutant, and in plants treated with L-kynurenine, a pharmacological inhibitor of auxin biosynthesis. Some of the patterning defects can be suppressed by synthetically elevated HD-ZIP III expression. Taken together, our results indicate that polar auxin transport, which was earlier shown to be required for protoxylem formation, is not sufficient to establish a proper xylem axis but that root-based auxin biosynthesis is additionally required.

  • 26.
    Wang, Yixin
    et al.
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
    Jin, Yi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortsäter, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Institute.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Jakobsson, Lars
    Karolinska Inst, Div Vasc Biol, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden..
    Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity2017In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 19, p. 3590-3601Article in journal (Refereed)
    Abstract [en]

    Tissue fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and its role in vessel maturation are unknown. Here, we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, Pdgfb overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and the low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate the requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels, and suggest an ECM-controlled checkpoint that prevents SMC investment of capillaries, which is a common feature in lymphedematous skin.

  • 27.
    Zhang, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Daubel, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stritt, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels2018In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 145, no 3, article id dev156745Article in journal (Refereed)
    Abstract [en]

    Maintenance of blood vessel integrity is crucial for vascular homeostasis and is mainly controlled at the level of endothelial cell (EC) junctions. Regulation of endothelial integrity has largely been investigated in the mature quiescent vasculature. Less is known about how integrity is maintained during vascular growth and remodeling involving extensive junctional reorganization. Here, we show that embryonic mesenteric blood vascular remodeling is associated with a transient loss of venous integrity and concomitant extravasation of red blood cells (RBCs), followed by their clearance by the developing lymphatic vessels. In wild-type mouse embryos, we observed activated platelets extending filopodia at sites of inter-EC gaps. In contrast, embryos lacking the activatory C-type lectin domain family 1, member b (CLEC1B) showed extravascular platelets and an excessive number of RBCs associated with and engulfed by the first lymphatic EC clusters that subsequently form lumenized blood-filled vessels connecting to the lymphatic system. These results uncover novel functions of platelets in maintaining venous integrity and lymphatic vessels in clearing extravascular RBCs during developmental remodeling of the mesenteric vasculature. They further provide insight into how vascular abnormalities characterized by blood-filled lymphatic vessels arise.

1 - 27 of 27
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