Project

Back to overview

Regulation of adult neural stem cell activity and fate downstream of Notch2 and Drosha

English title Regulation of adult neural stem cell activity and fate downstream of Notch2 and Drosha
Applicant Taylor Verdon
Number 162609
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Embryology, Developmental Biology
Start/End 01.10.2015 - 31.12.2018
Approved amount 678'000.00
Show all

All Disciplines (5)

Discipline
Embryology, Developmental Biology
Genetics
Neurophysiology and Brain Research
Cellular Biology, Cytology
Molecular Biology

Keywords (5)

Hippocampus; Neurogenesis; Subventricular zone; Brain; Neural stem cells

Lay Summary (German)

Lead
Das Hirn von Säugern enthält Stammzellen, welche die unterschiedlichsten Zelltypen bilden können. Die Kapazität zur funktionalen Regeneration sowie zur physiologischen Generation neuer Neuronen, nach unfall- oder krankheitsbedingter Traumata, sind jedoch limitiert. In diesem Projekt werden die Mechanismen untersucht, welche Stammzellaktivität und Differenzierungsentscheide kontrollieren.
Lay summary

Die embryonale Entstehung des Hirns wird durch die Produktion von Neuronen und Gliazellen aus einem Reservoir von neuronalen Stammzellen reguliert. Fehlfunktionen neuronaler Stammzellen könnten eine der Ursachen für angeborene Fehlbildungen, neuronale Abnormitäten und psychologische Störungen im Menschen sein. Stammzellen bleiben in bestimmten Regionen des ausgewachsenen Säugetierhirns erhalten und sind somit eine mögliche Quelle neuer Zellen. Diese könnten nützlich sein im Kampf gegen Neurodegenerationen und Traumata. Neuronale Stammzellen sind jedoch nicht im Stande neue Zellen zu bilden um jene zu ersetzen die durch Läsion oder Krankheit verloren gehen. Dieses Projekt hat das Ziel die molekularen Kontrollmechanismen neuronaler Stammzellen zu verstehen und zu begreifen wie diese Signale durch Krankheit und Alterung beeinflusst werden. In den letzten Jahren hat unsere Gruppe erforscht welche Mechanismen den Erhalt neuronaler Stammzellen regulieren und zur Generation von Neuronen und Gliazellen führen. Unsere zukünftigen Experimente zielen darauf ab diese beschriebenen molekularen Vorgänge der Genregulation, welche den Prozess der Differenzierung von Stammzellen kontrollieren, noch besser zu verstehen. Mit Hilfe modernster molekularer Genetik sollen Interaktionspartner dieser Mechanismen entdeckt werden in der Hoffnung Moleküle zu identifizieren welche zur therapeutischen Intervention genutzt werden können.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das bessere Verständis der Aktivierung und des Differenzierungspotentials neuronaler Stammzellen im entwickelnden sowie im erwachsenen Hirn, könnten weitreichende Implikationen für Therapiemöglichkeiten am Menschen und für die mögliche Regeneration des Hirns haben. 

 

Direct link to Lay Summary Last update: 02.10.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons
Vogt Miriam A., Ehsaei Zahra, Knuckles Philip, Higginbottom Adrian, Helmbrecht Michaela S., Kunath Tilo, Eggan Kevin, Williams Luis A., Shaw Pamela J., Wurst Wolfgang, Floss Thomas, Huber Andrea B., Taylor Verdon (2018), TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons, in Scientific Reports, 8(1), 8097-8097.
Molecular Mechanisms of Notch Signaling
Engler Anna, Zhang Runrui, Taylor Verdon (2018), Molecular Mechanisms of Notch Signaling, Springer International Publishing, Cham.
Notch: an interactive player in neurogenesis and disease
Zhang Runrui, Engler Anna, Taylor Verdon (2018), Notch: an interactive player in neurogenesis and disease, in Cell and Tissue Research, 371(1), 73-89.
Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone
Engler Anna, Rolando Chiara, Giachino Claudio, Saotome Ichiko, Erni Andrea, Brien Callum, Zhang Runrui, Zimber-Strobl Ursula, Radtke Freddy, Artavanis-Tsakonas Spyros, Louvi Angeliki, Taylor Verdon (2018), Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone, in Cell Reports, 22(4), 992-1002.
Expansion of human midbrain floor plate progenitors from induced pluripotent stem cells increases dopaminergic neuron differentiation potential
Fedele Stefania, Collo Ginetta, Behr Katharina, Bischofberger Josef, Müller Stephan, Kunath Tilo, Christensen Klaus, Gündner Anna Lisa, Graf Martin, Jagasia Ravi, Taylor Verdon (2017), Expansion of human midbrain floor plate progenitors from induced pluripotent stem cells increases dopaminergic neuron differentiation potential, in Scientific Reports, 7(1), 6036-6036.
Non-canonical post-transcriptional RNA regulation of neural stem cell potential
Rolando Chiara, Taylor Verdon (2017), Non-canonical post-transcriptional RNA regulation of neural stem cell potential, in Brain Plasticity, 3(1), 111-116.
The E2A splice variant E47 regulates the differentiation of projection neurons via p57(KIP2) during cortical development
Pfurr Sabrina, Chu Yu-Hsuan, Bohrer Christian, Greulich Franziska, Beattie Robert, Mammadzada Könül, Hils Miriam, Arnold Sebastian J., Taylor Verdon, Schachtrup Kristina, Uhlenhaut N. Henriette, Schachtrup Christian (2017), The E2A splice variant E47 regulates the differentiation of projection neurons via p57(KIP2) during cortical development, in Development, 144(21), 3917-3931.
Differential interactions between Notch and ID factors control neurogenesis by modulating Hes factor autoregulation
Boareto Marcelo, Iber Dagmar, Taylor Verdon (2017), Differential interactions between Notch and ID factors control neurogenesis by modulating Hes factor autoregulation, in Development, 144(19), 3465-3474.
Baculovirus-based genome editing in primary cells
Mansouri Maysam, Ehsaei Zahra, Taylor Verdon, Berger Philipp (2017), Baculovirus-based genome editing in primary cells, in Plasmid, 90, 5-9.
Highly efficient baculovirus-mediated multigene delivery in primary cells
Mansouri Maysam, Bellon-Echeverria Itxaso, Rizk Aurélien, Ehsaei Zahra, Cianciolo Cosentino Chiara, Silva Catarina S., Xie Ye, Boyce Frederick M., Davis M. Wayne, Neuhauss Stephan C. F., Taylor Verdon, Ballmer-Hofer Kurt, Berger Imre, Berger Philipp (2016), Highly efficient baculovirus-mediated multigene delivery in primary cells, in Nature Communications, 7(1), 11529-11529.
Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB
Rolando Chiara, Erni Andrea, Grison Alice, Beattie Robert, Engler Anna, Gokhale Paul J., Milo Marta, Wegleiter Thomas, Jessberger Sebastian, Taylor Verdon (2016), Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB, in Cell Stem Cell, 19(5), 653-662.
A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes
Giachino Claudio, Boulay Jean-Louis, Ivanek Robert, Alvarado Alvaro, Tostado Cristobal, Lugert Sebastian, Tchorz Jan, Coban Mustafa, Mariani Luigi, Bettler Bernhard, Lathia Justin, Frank Stephan, Pfister Stefan, Kool Marcel, Taylor Verdon (2015), A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes, in Cancer Cell, 28(6), 730-742.
Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation PotentialAdult Human Brain-Derived Pericytes
Lojewski Xenia, Srimasorn Sumitra, Rauh Juliane, Francke Silvan, Wobus Manja, Taylor Verdon, Araúzo-Bravo Marcos J., Hallmeyer-Elgner Susanne, Kirsch Matthias, Schwarz Sigrid, Schwarz Johannes, Storch Alexander, Hermann Andreas (2015), Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation PotentialAdult Human Brain-Derived Pericytes, in STEM CELLS Translational Medicine, 4(10), 1223-1233.
Notch-Tnf signalling is required for development and homeostasis of arterial valves
Wang Yidong, Wu Bingruo, Farrar Emily, Lui Wendy, Lu Pengfei, Zhang Donghong, Alfieri Christina M., Mao Kai, Chu Ming, Yang Di, Xu Di, Rauchman Michael, Taylor Verdon, Conway Simon J., Yutzey Katherine E., Butcher Jonathan T., Zhou Bin (2015), Notch-Tnf signalling is required for development and homeostasis of arterial valves, in European Heart Journal, ehv520-ehv520.
Transcriptional Hallmarks of Heterogeneous Neural Stem Cell Niches of the Subventricular ZoneRegional Transcriptome of the Subventricular Zone
Azim Kasum, Hurtado-Chong Anahí, Fischer Bruno, Kumar Nitin, Zweifel Stefan, Taylor Verdon, Raineteau Olivier (2015), Transcriptional Hallmarks of Heterogeneous Neural Stem Cell Niches of the Subventricular ZoneRegional Transcriptome of the Subventricular Zone, in STEM CELLS, 33(7), 2232-2242.
Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth
Moretti Francesca, Rolando Chiara, Winker Moritz, Ivanek Robert, Rodriguez Javier, Von Kriegsheim Alex, Taylor Verdon, Bustin Michael, Pertz Olivier (2015), Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth, in Molecular and Cellular Biology, 35(11), 2035-2050.
Striatal astrocytes produce neuroblasts in an excitotoxic model of Huntington's disease
Nato G., Caramello A., Trova S., Avataneo V., Rolando C., Taylor V., Buffo A., Peretto P., Luzzati F. (2015), Striatal astrocytes produce neuroblasts in an excitotoxic model of Huntington's disease, in Development, 142(5), 840-845.
Early phenotypic asymmetry of sister oligodendrocyte progenitor cells after mitosis and its modulation by aging and extrinsic factorsSister OPC Asymmetry after Mitosis
Boda Enrica, Di Maria Silvia, Rosa Patrizia, Taylor Verdon, Abbracchio Maria P., Buffo Annalisa (2015), Early phenotypic asymmetry of sister oligodendrocyte progenitor cells after mitosis and its modulation by aging and extrinsic factorsSister OPC Asymmetry after Mitosis, in Glia, 63(2), 271-286.

Collaboration

Group / person Country
Types of collaboration
Prof. Freddy Radtke/EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jorn Walter/University of Saarland Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Philip Berger/PSI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Mihaela Zavolan/University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dagmar Iber/ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Erik van Nimwegen/University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Sebastian Jessberger/University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Francois Guillemot/Crick Institute London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Synapsis Forum 2018 Talk given at a conference Mechanism of the TDP-43 p53 axis in inducing neuronal death in Frontotemporal Lobular Degeneration 12.11.2018 Bern, Switzerland Taylor Verdon;
EMBO|EMBL Symposium: The Complex Life of RNA Poster Post-transcriptional regulation of metabolic functions in astrocytes during brain ageing 03.11.2018 Heidelberg, Germany Rolando Chiara;
Translational Neuroscience Seminar Series Individual talk Control of stem cell fate in the brain: From niche to epigenetics 17.10.2018 Mainz, Germany Taylor Verdon;
Stem Cell Talk given at a conference Impact of Stem Cell Research and the Swiss Landscape 11.10.2018 Bern, Switzerland Taylor Verdon;
The Notch Meeting X Talk given at a conference Notch signalling in the control of neural stem cell activation and quiescence 01.10.2018 Athens, Greece Taylor Verdon;
National Congress of the Spanish Neuroscience Society Talk given at a conference Systems Biology Of Telencephalon Neurogenesis 27.09.2018 Alicante, Spain Taylor Verdon;
Neurodevelopment and Vulnerability of the Central Nervous System Individual talk Notch Control of Stem Cell Quiescence in Brain Homeostasis 19.09.2018 Erlangen, Germany Taylor Verdon;
Gene regulatory mechanisms in neural fate decisions. EMBO Conference Talk given at a conference Transcriptional Dynamics in Cortical Development 01.09.2018 Alicante, Spain Taylor Verdon;
Stem Cell Conference Basel 2018: Stem Cell Dynamics Throughout Life: From Development to the Adult Poster Notch2 signaling regulates cell cycle genes and Id4 to maintain neural stem cell quiescence in the adult hippocampus 29.08.2018 Basel, Switzerland Zhang Runrui;
Gordon Research Conference: Notch Signaling in Development, Regeneration and Disease Talk given at a conference Notch Control of Stem Cell Quiescence in Brain Homeostasis and Glioma 22.07.2018 Bates College, United States of America Taylor Verdon;
Emerging Roles of non-coding RNAs in nervous system development, plasticity and disease Talk given at a conference Drosha: A master regulator of neural stem cell fate 21.06.2018 Marburg, Germany Taylor Verdon;
RNA UK 2018 Poster Drosha interactome post-transcriptionally regulates neural stem cell fate 26.01.2018 Windermere, Great Britain and Northern Ireland Iffländer Niklas;
XIII European Meeting on Glial Cells in Health and Disease Poster Post-transcriptional RNA regulation in adult neurogenesis and brain homeostasis 08.06.2017 Edinburgh, Great Britain and Northern Ireland Rolando Chiara;
Young Glia Meeting Talk given at a conference Post-transcriptional RNA regulation of neural stem cell potential keeps oligodendrocytic differentiation in check 09.02.2017 Erlangen, Germany Rolando Chiara;
Society For Neuroscience Meeting 2016 Talk given at a conference Drosha-mediated post-transcriptional regulation of multi-lineage potential of hippocampal stem cells 12.11.2016 San Diego, United States of America Rolando Chiara;
Neurodevelopment and Vulnerability of the Central Nervous System seminar series Individual talk Neural stem cell quiescence 02.11.2016 Erlangen, Germany Taylor Verdon;
EMBO Workshop: Nuclear Function and Cell Fate Choice Poster Notch2 maintains adult neural stem cell quiescence in the hippocampal subgranular zone 18.09.2016 Kyllini, Greece Zhang Runrui;
EMBO workshop: Nuclear function and cell fate choice Talk given at a conference Drosha regulates neural stem cell fate by non-canonical regulation of RNA stability 21.08.2016 Kyllini, Greece Taylor Verdon; Zhang Runrui;
7th Annual Conference on Stem Cell and Regenerative Medicine Talk given at a conference Regulation of hippocampal neural stem cell fate 04.08.2016 Manchester, Great Britain and Northern Ireland Taylor Verdon;
Gordon Research Seminar & Conference – Notch Signaling in Development, Regeneration & Disease Talk given at a conference Differential roles of Notch1 and Notch2 signaling in the adult murine brain 30.07.2016 Bates Cellege, United States of America Engler Anna;
Eurogenesis Meeting Talk given at a conference Drosha control of glial fate acquisition in the hippocampus 11.07.2016 Bordeaux, France Taylor Verdon;
SGMB, Multidisciplinary Module 2016 Talk given at a conference Controlling Neural Stem Cell Differentiation 17.06.2016 Freiburg, Germany Taylor Verdon;
ETH Neurobiology: Special guest seminar series Individual talk Mechanisms of TDP-43 induced cell death during neural development 03.05.2016 Zurich, Switzerland Taylor Verdon;
1st Neurogenesis meeting Talk given at a conference Regulation of Oligodendrocyte Differentiation in the Hippocampal Neurogenic Niche 03.03.2016 Cancun, Mexico Taylor Verdon;
Diss:kurs University of Basel Talk given at a conference Untangling Adult Neurogenesis, Notch by Notch 03.02.2016 Basel, Switzerland Engler Anna;
Center for Regenerative Therapies Dresden. Special guest seminar series Individual talk Regulation of neural stem cell fate: Between transcription and translation 23.10.2015 Dresden, Germany Taylor Verdon;
The Notch Meeting Talk given at a conference Differential roles of Notch1 or Notch2 signaling in the adult murine brain 04.10.2015 Athens, Greece Engler Anna;


Self-organised

Title Date Place
BSCN Annual Meeting 2017 07.04.2017 Basel, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Brain Awareness Week Western Switzerland International 2018
Talks/events/exhibitions Warum wir mit Tieren forschen – “Why we do animal experimentation" Western Switzerland German-speaking Switzerland International 2016

Associated projects

Number Title Start Funding scheme
143767 Analysis of RNA destabilization as a novel regulator of mammalian neurogenesis downstream of Notch in neural stem cells 01.10.2012 Project funding (Div. I-III)
182388 Drosha and its RNA binding partners in neurogenesis 01.01.2019 Project funding (Div. I-III)

Abstract

The regulation of neural stem cell (NSC) maintenance and differentiation is crucial for formation of the central nervous system (CNS). A detailed understanding of NSC biology has important implications for comprehending congenital brain malformations, age-related disorders, neurological diseases and regeneration. Established genetic tools, in vivo and in vitro experimental approaches for manipulation and lineage tracing, make neural progenitors an attractive experimental paradigm. The patterned and structured formation of the mammalian brain and positional fate restriction assists in the analysis of phenotypes and gene functions. Further, congenital brain malformations can often be traced to aberrant proliferation, differentiation or specification of neural progenitors. The production of new neurons also plays important roles in the adult mammalian brain. In rodents, neurons of the olfactory system are continually regenerated from the subventricular zone (SVZ), rebuilding complex multi-neuron circuits. New neurons in the hippocampal dentate gyrus (DG) are important for specific forms of memory and learning in mice. Although the role of neurogenesis in the human brain is debated, links to pathologies including epilepsy, depression and brain tumors underline the importance of understanding the mechanism controlling NSCs. The potential of NSC for regeneration and rejuvenation also emphasize a need to fill the gaps in our basic knowledge of NSC biology.My lab has focused on the role of Notch signaling in NSC maintenance1-4. By generating and combining transgenic mice with analysis of homeostasis, physical activity, degeneration, regeneration aging and in vitro approaches, we determined that NSCs are a heterogeneous cell population even within the same niche1,2,4-6. Recently, we found that the adult SVZ and DG contain active and dormant NSCs1,5-7. Active NSCs express brain lipid binding protein (BLBP), drive neurogenesis, and there loss is one potential cause of the age-dependent decline in neurogenesis. BLBP+ active NSCs have not been studied in detail, either during homeostasis, aging nor regeneration. We have generated tools including transgenic mice to study these active and dormant NSCs in greater detail. We will use these tools to continue to deepen our knowledge of NSCs in the brain. We will lineage trace different NSC populations in vivo, addressing dormant, quiescent and active NSCs and elucidating their roles in homeostasis and regeneration. We will study the effects that pathophysiological stimuli have on these NSC populations. Recently we found that active NSCs depend upon Notch1 but dormant NSCs do not. Dormant NSCs express Notch2 and Notch3, hence, we will assess the functions of Notch1, Notch2 and Notch3 in the different NSCs populations of the brain. The control of NSC activity and dormancy has clinical relevance for regeneration but also for rejuvenation to combat age-related disorders. We have generated transcription profiles of embryonic and adult Hes5::GFP+ NSCs and of Notch1-regulated genes in NSCs. Many components of the microRNA (miRNA) biogenesis pathway were present in these profiles. Therefore, we targeted the root of miRNA biogenesis, conditionally ablating key components of the miRNA microprocessor (MP) in forebrain NSCs. We established that the MP and Drosha, unlike Dicer, play a central role in regulating NSCs during development. An important function of the MP in NSCs is a novel miRNA-independent mechanism to directly target stem-loop hairpin structures in the Ngn2 mRNA. We will extend our previous findings of MP function in neurogenesis, identify novel targets of the MP and extend the analysis of MP function to active and dormant NSCs during aging and regeneration.
-