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  • 1.
    Azim, Kasum
    et al.
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University Mainz, Germany / Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Germany.
    Angonin, Diane
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Marcy, Guillaume
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Pieropan, Francesca
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Rivera, Andrea
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Donega, Vanessa
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Cantù, Claudio
    IMLS, University of Zurich, Zurich, Switzerland.
    Williams, Gareth
    Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, United Kingdom.
    Berninger, Benedikt
    Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University Mainz, Germany / Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Germany.
    Butt, Arthur M
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Raineteau, Olivier
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity2017In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, no 3, article id e2000698Article in journal (Refereed)
    Abstract [en]

    Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.

  • 2.
    Azim, Kasum
    et al.
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Fischer, Bruno
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Hurtado-Chong, Anahi
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Draganova, Kalina
    Institute of Anatomy, University of Zürich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zürich, Switzerland.
    Zemke, Martina
    Institute of Anatomy, University of Zürich, Switzerland.
    Sommer, Lukas
    Institute of Anatomy, University of Zürich, Switzerland.
    Butt, Arthur
    Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, Portsmouth University, United Kingdom.
    Raineteau, Olivier
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Stem Cell and Brain Research Institute, INSERMU846, Lyon, France, Universite de Lyon,Universite Lyon, France.
    Persistent Wnt/β‐Catenin Signaling Determines Dorsalization of the Postnatal Subventricular Zone and Neural Stem Cell Specification into Oligodendrocytes and Glutamatergic Neurons2014In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 32, no 5, p. 1301-1312Article in journal (Refereed)
    Abstract [en]

    In the postnatal and adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the main source of neural stem cells (NSCs) that generate olfactory neurons and oligodendrocytes (OLs), the myelinating cells of the CNS. Here, we provide evidence of a primary role for canonical Wnt/β-catenin signaling in regulating NSC fate along neuronal and oligodendroglial lineages in the postnatal SVZ. Our findings demonstrate that glutamatergic neuronal precursors (NPs) and oligodendrocyte precursors (OPs) are derived strictly from the dorsal SVZ (dSVZ) microdomain under the control of Wnt/β-catenin, whereas GABAergic NPs are derived mainly from the lateral SVZ (lSVZ) microdomain independent of Wnt/β-catenin. Transcript analysis of microdissected SVZ microdomains revealed that canonical Wnt/β-catenin signaling was more pronounced in the dSVZ microdomain. This was confirmed using the β-catenin-activated Wnt-reporter mouse and by pharmacological stimulation of Wnt/β-catenin by infusion of the specific glycogen synthase kinase 3β inhibitor, AR-A014418, which profoundly increased the generation of cycling cells. In vivo genetic/pharmacological stimulation or inhibition of Wnt/β-catenin, respectively, increased and decreased the differentiation of dSVZ-NSCs into glutamatergic NPs, and had a converse effect on GABAergic NPs. Activation of Wnt/β-catenin dramatically stimulated the generation of OPs, but its inhibition had no effect, indicating other factors act in concert with Wnt/β-catenin to fine tune oligodendrogliogenesis in the postnatal dSVZ. These results demonstrate a role for Wnt/β-catenin signaling within the dorsal microdomain of the postnatal SVZ, in regulating the genesis of glutamatergic neurons and OLs.

  • 3.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Bosè, Francesca
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy / Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Bianchi, Paola
    Haematology Unit 2, Unit of Physiopathology of Anaemia, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Reali, Eva
    Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Colzani, Maria Teresa
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Cantù, Ileana
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Barbarani, Gloria
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Witke, Walter
    Institut of Genetics, University of Bonn, Bonn, Germany.
    Spinardi, Laura
    Scientific Direction, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Ronchi, Antonella Ellena
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Defective Erythroid Maturation In Gelsolin Mutant Mice2012In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, no 7, p. 980-988Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: During late differentiation, erythroid cells undergo profound changes involving actin filament remodeling. One of the proteins controlling actin dynamics is gelsolin, a calcium-activated actin filament severing and capping protein. Gelsolin-null (Gsn(-/-)) mice generated in a C57BL/6 background are viable and fertile.1

    DESIGN AND METHODS: We analyzed the functional roles of gelsolin in erythropoiesis by: (i) evaluating gelsolin expression in murine fetal liver cells at different stages of erythroid differentiation (using reverse transcription polymerase chain reaction analysis and immunohistochemistry), and (ii) characterizing embryonic and adult erythropoiesis in Gsn(-/-) BALB/c mice (morphology and erythroid cultures).

    RESULTS: In the context of a BALB/c background, the Gsn(-/-) mutation causes embryonic death. Gsn(-/-) embryos show defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn(-/-) mice reaching adulthood fail to recover from phenylhydrazine-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays, E13.5 fetal liver Gsn(-/-) cells failed to undergo terminal maturation, a defect partially rescued by Cytochalasin D, and mimicked by administration of Jasplakinolide to the wild-type control samples.

    CONCLUSIONS: In BALB/c mice, gelsolin deficiency alters the equilibrium between erythrocyte actin polymerization and depolymerization, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn(-/-) mice lethality observed in mid-gestation.

  • 4.
    Cantù, Claudio
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Felker, Anastasia
    Univ Zurich, Switzerland.
    Zimmerli, Dario
    Univ Zurich, Switzerland.
    Prummel, Karin D.
    Univ Zurich, Switzerland.
    Cabello, Elena M.
    Univ Zurich, Switzerland.
    Chiavacci, Elena
    Univ Zurich, Switzerland; Int Ctr Genet Engn and Biotechnol ICGEB Trieste, Italy.
    Mendez-Acevedo, Kevin M.
    Max Delbruck Ctr Mol Med, Germany.
    Kirchgeorg, Lucia
    Univ Zurich, Switzerland.
    Burger, Sibylle
    Univ Zurich, Switzerland.
    Ripoll, Jorge
    Univ Carlos III Madrid, Spain.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Vilain, Nathalie
    Ecole Polytech Fed Lausanne, Switzerland.
    Aguet, Michel
    Ecole Polytech Fed Lausanne, Switzerland.
    Burger, Alexa
    Univ Zurich, Switzerland.
    Panakova, Daniela
    Max Delbruck Ctr Mol Med, Germany; Deutsch Zentrum Herz Kreislauf Forsch DZHK, Germany.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Mosimann, Christian
    Univ Zurich, Switzerland.
    Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/beta-catenin signaling2018In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 32, no 21-22, p. 1443-1458Article in journal (Refereed)
    Abstract [en]

    Bcl9 and Pygopus (Pygo) are obligate Wnt/beta-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, beta-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the beta-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective beta-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.

  • 5.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Grande, Vito
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Alborelli, Ilaria
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Cassinelli, Letizia
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Cantù, Ileana
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Colzani, Maria Teresa
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Ierardi, Rossella
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
    Ronzoni, Luisa
    Dipartimento di Medicina Interna, Università di Milano, Fondazione Policlinico Mangiagalli, Regina Elena, IRCCS, Milano, Italy.
    Cappellini, Maria Domenica
    Dipartimento di Medicina Interna, Università di Milano, Fondazione Policlinico Mangiagalli, Regina Elena, IRCCS, Milano, Italy.
    Ferrari, Giuliana
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, 20132 Milan // Vita-Salute San Raffaele University, Milan, Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Ronchi, Antonella
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    A highly conserved SOX6 double binding site mediates SOX6 gene downregulation in erythroid cells2011In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 2, p. 486-501Article in journal (Refereed)
    Abstract [en]

    The Sox6 transcription factor plays critical roles in various cell types, including erythroid cells. Sox6-deficient mice are anemic due to impaired red cell maturation and show inappropriate globin gene expression in definitive erythrocytes. To identify new Sox6 target genes in erythroid cells, we used the known repressive double Sox6 consensus within the εy-globin promoter to perform a bioinformatic genome-wide search for similar, evolutionarily conserved motifs located within genes whose expression changes during erythropoiesis. We found a highly conserved Sox6 consensus within the Sox6 human gene promoter itself. This sequence is bound by Sox6 in vitro and in vivo, and mediates transcriptional repression in transient transfections in human erythroleukemic K562 cells and in primary erythroblasts. The binding of a lentiviral transduced Sox6FLAG protein to the endogenous Sox6 promoter is accompanied, in erythroid cells, by strong downregulation of the endogenous Sox6 transcript and by decreased in vivo chromatin accessibility of this region to the PstI restriction enzyme. These observations suggest that the negative Sox6 autoregulation, mediated by the double Sox6 binding site within its own promoter, may be relevant to control the Sox6 transcriptional downregulation that we observe in human erythroid cultures and in mouse bone marrow cells in late erythroid maturation.

  • 6.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Ierardi, Rossella
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milano, Italy.
    Alborelli, Ilaria
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Fugazza, Cristina
    John Radcliffe Hospital, Molecular Hematology Unit, Oxford, United Kingdom.
    Cassinelli, Letizia
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Piconese, Silvia
    Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
    Bosè, Francesca
    5INGM-Fondazione Istituto Nazionale di Genetica molecolare, Milano, Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Ferrari, Giuliana
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milano, Italy / Universita` Vita-Salute San Raffaele, Milano, Italy.
    Ronchi, Antonella
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Sox6 enhances erythroid differentiation in human erythroid progenitors.2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 13, p. 3669-79Article in journal (Refereed)
    Abstract [en]

    Sox6 belongs to the Sry (sex-determining region Y)-related high-mobility-group-box family of transcription factors, which control cell-fate specification of many cell types. Here, we explored the role of Sox6 in human erythropoiesis by its overexpression both in the erythroleukemic K562 cell line and in primary erythroid cultures from human cord blood CD34+ cells. Sox6 induced significant erythroid differentiation in both models. K562 cells underwent hemoglobinization and, despite their leukemic origin, died within 9 days after transduction; primary erythroid cultures accelerated their kinetics of erythroid maturation and increased the number of cells that reached the final enucleation step. Searching for direct Sox6 targets, we found SOCS3 (suppressor of cytokine signaling-3), a known mediator of cytokine response. Sox6 was bound in vitro and in vivo to an evolutionarily conserved regulatory SOCS3 element, which induced transcriptional activation. SOCS3 overexpression in K562 cells and in primary erythroid cells recapitulated the growth inhibition induced by Sox6, which demonstrates that SOCS3 is a relevant Sox6 effector.

  • 7.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Pagella, Pierfrancesco
    Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
    Shajiei, Tania D
    Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Mitsiadis, Thimios A
    Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
    A cytoplasmic role of Wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation.2017In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 465, article id eaah4598Article in journal (Refereed)
    Abstract [en]

    Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate with β-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind β-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. We showed that Bcl9 and Bcl9l function in the cytoplasm during tooth enamel formation in a manner that is independent of Wnt-stimulated β-catenin-dependent transcription. Bcl9, Bcl9l, and Pygo2 localized mainly to the cytoplasm of the epithelial-derived ameloblasts, the cells responsible for enamel production. In ameloblasts, Bcl9 interacted with proteins involved in enamel formation and proteins involved in exocytosis and vesicular trafficking. Conditional deletion of both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in mice produced teeth with defective enamel that was bright white and deficient in iron, which is reminiscent of human tooth enamel pathologies. Overall, our data revealed that these proteins, originally defined through their function as β-catenin transcriptional cofactors, function in odontogenesis through a previously uncharacterized cytoplasmic mechanism, revealing that they have roles beyond that of transcriptional cofactors.

  • 8.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, University of Zurich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, Switzerland.
    A RING finger to wed TCF and β-catenin2013In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 14, no 4, p. 295-296Article in journal (Refereed)
  • 9.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
    Unexpected survival of mice carrying a mutation in Pygo2 that strongly reduces its binding to Bcl9/9l2016In: Matters Select, ISSN 2297-9239Article in journal (Refereed)
    Abstract [en]

    Pygopus is a transcriptional activator important for the Wnt signaling pathway. It binds to the beta-catenin transcriptional complex via the adaptor proteins Bcl9 and Bcl9l (Bcl9/9l). This complex is considered to be a suitable target for the treatment of tumors that display activated Wnt signaling. In the mouse, there are two Pygopus-encoding genes, Pygo1 and Pygo2 (Pygo1/2), with the latter playing a major role. Here we introduce a single amino acid substitution in Pygo2, which was previously shown to abrogate binding to Bcl9/9l, and cause lethality in Drosophila melanogaster. We confirm that mutant Pygo2 protein fails in interacting with Bcl9 but, unexpectedly, homozygous mice with this mutation are viable and fertile, even when this mutant allele is combined with a null mutation of the potentially redundant Pygo1. Based on this observation, we conjecture that the Pygo-Bcl9/9l interaction requires scant affinity in vivo to fulfill developmental functions and thrust forward the notion that this interaction surface could be targeted in cancer therapy without major consequences on homeostatic functions.

  • 10.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Moor, Andreas
    Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, 1011 Lausanne, Switzerland.
    Aguet, Michel
    Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, 1011 Lausanne, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development.2014In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 28, no 17, p. 1879-84Article in journal (Refereed)
    Abstract [en]

    Bcl9 and Bcl9l (Bcl9/9l) encode Wnt signaling components that mediate the interaction between β-catenin and Pygopus (Pygo) via two evolutionarily conserved domains, HD1 and HD2, respectively. We generated mouse strains lacking these domains to probe the β-catenin-dependent and β-catenin-independent roles of Bcl9/9l and Pygo during mouse development. While lens development is critically dependent on the presence of the HD1 domain, it is not affected by the lack of the HD2 domain, indicating that Bcl9/9l act in this context in a β-catenin-independent manner. Furthermore, we uncover a new regulatory circuit in which Pax6, the master regulator of eye development, directly activates Bcl9/9l transcription.

  • 11.
    Doumpas, Nikolaos
    et al.
    Univ Zurich, Switzerland.
    Lampart, Franziska
    Univ Zurich, Switzerland.
    Robinson, Mark D.
    Univ Zurich, Switzerland.
    Lentini, Antonio
    Univ Zurich, Switzerland.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    TCF/LEF dependent and independent transcriptional regulation of Wnt/beta-catenin target genes2019In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 38, no 2, article id e98873Article in journal (Refereed)
    Abstract [en]

    During canonical Wnt signalling, the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors.

  • 12.
    Draganova, Kalina
    et al.
    Cell and Developmental Biology Division, Institute of Anatomy, University of Zurich, Switzerland.
    Zemke, Martina
    Cell and Developmental Biology Division, Institute of Anatomy, Zurich, University of Zurich,Zurich, Switzerland.
    Zurkirchen, Luis
    Cell and Developmental Biology Division, Institute of Anatomy, Zurich, University of Zurich,Zurich, Switzerland.
    Valenta, Tomas
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Cantù, Claudio
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Okoniewski, Michal
    Functional Genomics Center, University of Zurich,Zurich, Switzerland.
    Schmid, Marie-Theres
    Institute for Stem Cell Research, Helmholtz Centre Munich, German Research Center for Environmental Health(GmbH), Neuherberg, Munich, Germany.
    Hoffmans, Raymond
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Götz, Magdalena
    Institute for Stem Cell Research, Helmholtz Centre Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Munich, Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Cluster for Systems Neurology (SyNergy), Munich, Germany.
    Basler, Konrad
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Sommer, Lukas
    Cell and Developmental Biology Division, Institute of Anatomy, University of Zurich, Switzerland.
    Wnt/β‐Catenin Signaling Regulates Sequential Fate Decisions of Murine Cortical Precursor Cells2015In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 33, no 1, p. 170-182Article in journal (Refereed)
    Abstract [en]

    The fate of neural progenitor cells (NPCs) is determined by a complex interplay of intrinsic programs and extrinsic signals, very few of which are known. β-Catenin transduces extracellular Wnt signals, but also maintains adherens junctions integrity. Here, we identify for the first time the contribution of β-catenin transcriptional activity as opposed to its adhesion role in the development of the cerebral cortex by combining a novel β-catenin mutant allele with conditional inactivation approaches. Wnt/β-catenin signaling ablation leads to premature NPC differentiation, but, in addition, to a change in progenitor cell cycle kinetics and an increase in basally dividing progenitors. Interestingly, Wnt/β-catenin signaling affects the sequential fate switch of progenitors, leading to a shortened neurogenic period with decreased number of both deep and upper-layer neurons and later, to precocious astrogenesis. Indeed, a genome-wide analysis highlighted the premature activation of a corticogenesis differentiation program in the Wnt/β-catenin signaling-ablated cortex. Thus, β-catenin signaling controls the expression of a set of genes that appear to act downstream of canonical Wnt signaling to regulate the stage-specific production of appropriate progenitor numbers, neuronal subpopulations, and astroglia in the forebrain.

  • 13.
    Kabakci, Zeynep
    et al.
    Univ Zurich, Switzerland.
    Kappeli, Simon
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Konig, Christiane
    Univ Zurich, Switzerland.
    Toggweiler, Janine
    Univ Zurich, Switzerland.
    Gentili, Christian
    Univ Zurich, Switzerland.
    Ribaudo, Giovanni
    Univ Padua, Italy.
    Zagotto, Giuseppe
    Univ Padua, Italy.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Pinna, Lorenzo A.
    Univ Padua, Italy.
    Cozza, Giorgio
    Univ Padua, Italy.
    Ferrari, Stefano
    Univ Zurich, Switzerland.
    Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 1335Article in journal (Refereed)
    Abstract [en]

    CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, the compounds induced differentiation, accompanied by decreased stemness properties, in intestinal crypt stem cell-derived Apc/K-Ras-mutant mouse organoids, and led to tumor regression and reduction of metastatic potential in zebrafish embryo xenografts used as in vivo model.

  • 14.
    Mitsiadis, Thimios A.
    et al.
    Orofacial Development and Regeneration, Centre for Dental Medicine, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jimenez-Rojo, Lucia
    Orofacial Development and Regeneration, Centre for Dental Medicine, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Editorial: Signaling Pathways in Developing and Pathological Tissues and Organs of the Craniofacial Complex2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, p. 1-3, article id 1015Article in journal (Refereed)
  • 15.
    Mitsiadis, Thimios A
    et al.
    Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, Medical Faculty, University of Zurich, Zurich, Switzerland.
    Pagella, Pierfrancesco
    Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, Medical Faculty, University of Zurich, Zurich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
    Early Determination of the Periodontal Domain by the Wnt-Antagonist Frzb/Sfrp3.2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 936Article in journal (Refereed)
    Abstract [en]

    Odontogenesis results from the continuous and reciprocal interaction between cells of the oral epithelium and cranial neural crest-derived mesenchyme. The canonical Wnt signaling pathway plays a fundamental role in mediating these interactions from the earliest stages of tooth development. Here we analyze by in situ hybridization the expression patterns of the extracellular Wnt antagonist Frzb/Sfrp3. Although Frzb is expressed in dental mesenchymal cells from the earliest stages of odontogenesis, its expression is absent from a tiny population of mesenchymal cells immediately adjacent to the invaginating dental epithelium. Cell proliferation studies using BrdU showed that the Frzb expressing and Frzb non-expressing cell populations display different proliferative behavior during the initial stages of odontogenesis. DiI-mediated cell-fate tracing studies demonstrated that the Frzb expressing cells contribute to the formation of the dental follicle, the future periodontium. In contrast, the Frzb non-expressing cells give rise to the dental pulp. The present results indicate that Frzb is discriminating the presumptive periodontal territory from the rest of the dental mesenchyme from the very beginning of odontogenesis, where it might act as a barrier for the diffusion of Wnt molecules, thus regulating the activation of Wnt-dependent transcription within dental tissues.

  • 16.
    Moor, Andreas E.
    et al.
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Anderle, Pascale
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Rodriguez, Patrick
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Wiedemann, Norbert
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Baruthio, Frédérique
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Deka, Jürgen
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    André, Sylvie
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Moor, Matthias B
    Department of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland.
    Győrffy, Balázs
    MTA TTK Lendület Cancer Biomarker Research Group, 2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.
    Barras, David
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
    Delorenzi, Mauro
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, CH-1066 Lausanne, Switzerland; Oncology Department, University of Lausanne, CH-1015 Lausanne, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Aguet, Michel
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer2015In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 2, no 12, p. 1932-1943Article in journal (Refereed)
    Abstract [en]

    BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.

  • 17.
    Pagella, Pierfrancesco
    et al.
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Cantù, Claudio
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Mitsiadis, Thimios A.
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Linking dental pathologies and cancer via Wnt signalling2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99213-99214Article in journal (Refereed)
  • 18.
    Salazar, Valerie S.
    et al.
    Harvard Sch Dent Med, MA 02115 USA; Univ Zurich, Switzerland.
    Capelo, Luciane P.
    Harvard Sch Dent Med, MA 02115 USA; Univ Fed Sao Paulo, Brazil.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Zimmerli, Dario
    Univ Zurich, Switzerland.
    Gosalia, Nehal
    Regeneron Pharmaceut, NY USA.
    Pregizer, Steven
    Harvard Sch Dent Med, MA 02115 USA.
    Cox, Karen
    Harvard Sch Dent Med, MA 02115 USA.
    Ohte, Satoshi
    Harvard Sch Dent Med, MA 02115 USA; Kitasato Univ, Japan.
    Feigenson, Marina
    Harvard Sch Dent Med, MA 02115 USA.
    Gamer, Laura
    Harvard Sch Dent Med, MA 02115 USA.
    Nyman, Jeffry S.
    Vanderbilt Univ, TN USA.
    Carey, David J.
    Geisinger Hlth Syst, PA USA.
    Economides, Aris
    Regeneron Pharmaceut, NY USA.
    Basler, Konrad
    Harvard School of Dental Medicine, Boston, United States.
    Rosen, Vicki
    Harvard Sch Dent Med, MA 02115 USA.
    Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e42386Article in journal (Refereed)
    Abstract [en]

    Two decades after signals controlling bone length were discovered, the endogenous ligands determining bone width remain unknown. We show that postnatal establishment of normal bone width in mice, as mediated by bone-forming activity of the periosteum, requires BMP signaling at the innermost layer of the periosteal niche. This developmental signaling center becomes quiescent during adult life. Its reactivation however, is necessary for periosteal growth, enhanced bone strength, and accelerated fracture repair in response to bone-anabolic therapies used in clinical orthopedic settings. Although many BMPs are expressed in bone, periosteal BMP signaling and bone formation require only Bmp2 in the Prx1-Cre lineage. Mechanistically, BMP2 functions downstream of Lrp5/6 pathway to activate a conserved regulatory element upstream of Sp7 via recruitment of Smad1 and Grhl3. Consistent with our findings, human variants of BMP2 and GRHL3 are associated with increased risk of fractures.

  • 19.
    Valenta, Tomas
    et al.
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Degirmenci, Bahar
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Moor, Andreas E
    Department of Molecular Cell Biology, Wolfson Building 623, Weizmann Institute of Science, Rehovot 76100, Israel.
    Herr, Patrick
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Moor, Matthias B
    Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Aguet, Michel
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Wnt Ligands Secreted by Subepithelial Mesenchymal Cells Are Essential for the Survival of Intestinal Stem Cells and Gut Homeostasis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 15, no 5, p. 911-918, article id S2211-1247(16)30394-1Article in journal (Refereed)
    Abstract [en]

    Targeting of Wnt signaling represents a promising anti-cancer therapy. However, the consequences of systemically attenuating the Wnt pathway in an adult organism are unknown. Here, we globally prevent Wnt secretion by genetically ablating Wntless. We find that preventing Wnt signaling in the entire body causes mortality due to impaired intestinal homeostasis. This is caused by the loss of intestinal stem cells. Reconstitution of Wnt/β-catenin signaling via delivery of external Wnt ligands prolongs the survival of intestinal stem cells and reveals the essential role of extra-epithelial Wnt ligands for the renewal of the intestinal epithelium. Wnt2b is a key extra-epithelial Wnt ligand capable of promoting Wnt/β-catenin signaling and intestinal homeostasis. Wnt2b is secreted by subepithelial mesenchymal cells that co-express either Gli1 or Acta2. Subepithelial mesenchymal cells expressing high levels of Wnt2b are predominantly Gli1 positive.

  • 20.
    Zimmerli, Dario
    et al.
    Univ Zurich, Switzerland.
    Cecconi, Virginia
    Univ Zurich, Switzerland.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Restivo, Gaetana
    Univ Hosp Zurich, Switzerland.
    Hafner, Jurg
    Univ Hosp Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    van den Broek, Maries
    Univ Zurich, Switzerland.
    WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma2018In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 27, p. 3753-3762Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/beta-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

  • 21.
    Zimmerli, Dario
    et al.
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein-protein interfaces of nuclear factors2017In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 174, no 24, p. 4600-4610Article in journal (Refereed)
    Abstract [en]

    Mutations in components of the Wnt pathways are a frequent cause of many human diseases, particularly cancer. Despite the fact that a causative link between aberrant Wnt signalling and many types of human cancers was established more than a decade ago, no Wnt signalling inhibitors have made it into the clinic so far. One reason for this is that no pathway-specific kinase is known. Additionally, targeting the protein-protein interactions needed to transduce the signal has not met with success so far. Complicating the search for and use of inhibitors is the complexity of the cascades triggered by the Wnts and their paramount biological importance. Wnt/β-catenin signalling is involved in virtually all aspects of embryonic development and in the control of the homeostasis of adult tissues. Encouragingly, however, in recent years, first successes with Wnt-pathway inhibitors have been reported in mouse models of disease. In this review, we summarize possible roads to follow during the quest to pharmacologically modulate the Wnt signalling pathway in cancer.

  • 22.
    Zurkirchen, Luis
    et al.
    Univ Zurich, Switzerland.
    Varum, Sandra
    Univ Zurich, Switzerland.
    Giger, Sonja
    Univ Zurich, Switzerland.
    Klug, Annika
    Univ Zurich, Switzerland.
    Hausel, Jessica
    Univ Zurich, Switzerland.
    Bossart, Raphael
    Univ Zurich, Switzerland.
    Zemke, Martina
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Atak, Zeynep Kalender
    Katholieke Univ Leuven, Belgium.
    Zamboni, Nicola
    Swiss Fed Inst Technol, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Sommer, Lukas
    Univ Zurich, Switzerland.
    Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2192Article in journal (Refereed)
    Abstract [en]

    The transcription factor Yin Yang 1 (YY1) plays an important role in human disease. It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. Here, we show that Yy1 controls murine cerebral cortex development in a stage-dependent manner. By regulating a wide range of metabolic pathways and protein translation, Yy1 maintains proliferation and survival of neural progenitor cells (NPCs) at early stages of brain development. Despite its constitutive expression, however, the dependence on Yy1 declines over the course of corticogenesis. This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Thus, our study unravels a novel role for Yy1 as a stage-dependent regulator of brain development and shows that biosynthetic demands of NPCs dynamically change throughout development.

1 - 22 of 22
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