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Analysis of RNA destabilization as a novel regulator of mammalian neurogenesis downstream of Notch in neural stem cells

English title Analysis of RNA destabilization as a novel regulator of mammalian neurogenesis downstream of Notch in neural stem cells
Applicant Taylor Verdon
Number 143767
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 01.10.2012 - 30.09.2015
Approved amount 544'800.00
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All Disciplines (5)

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

Keywords (5)

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

Lay Summary (English)

Lead
Lay summary

The brain is generated by the regulated production of neurons and glial cell from pools of neural stem cells. Defects in neural stem cell function may be responsible for some congenital brain malformations, neurological abnormalities and psychological disorders in humans. Importantly, stem cells remain in some regions of the adult mammalian brain but fail to regenerate new brain tissue after injury or during disease. We aim to understand the molecular mechanisms that control the regulation of neural stem cells and how these signals may be influenced by disease and aging. Over the past few years, we have identified a striking diversity in the neural stem cell pools within the adult mammalian brain. Using genetic analyses we are now able to identify, trace and isolate these different neural stem cell populations and to study their transition between active and quiescent states. Recently, we have identified a novel mechanism of neural stem cell regulation whereby the expression of key regulatory proteins is directly controlled by mRNA destabilization in addition to gene expression. We plan experiments to study in more detail the molecular machinery that controls the process of neural stem cell differentiation beyond the level of the gene. We will identify other targets of this molecular pathway through state-of-the-art molecular genetics. In addition, we will study the signaling mechanisms that control differences in stem cell activity during aging and disease. A deeper understanding of the regulatory mechanisms that control the activity of neural stem cells in the developing and adult brain and their differentiation potential could have wide reaching implications for human therapy and potentially brain regeneration.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Early Phenotypic Asymmetry of Sister Oligodendrocyte Progenitor Cells After Mitosis and Its Modulation by Aging and Extrinsic Factors
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 Factors, in GLIA, 63(2), 271-286.
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.
Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential
Lojewski Xenia, Srimasorn Sumitra, Rauh Juliane, Francke Silvan, Wobus Manja, Taylor Verdon, Arauzo-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 Potential, in STEM CELLS TRANSLATIONAL MEDICINE, 4(10), 1223-1233.
Striatal astrocytes produce neuroblasts in an excitotoxic model of Huntington's disease
Nato Giulia, Caramello Alessia, Trova Sara, Avataneo Valeria, Rolando Chiara, Taylor Verdon, Buffo Annalisa, Peretto Paolo, Luzzati Federico (2015), Striatal astrocytes produce neuroblasts in an excitotoxic model of Huntington's disease, in DEVELOPMENT, 142(5), 840-845.
Transcriptional Hallmarks of Heterogeneous Neural Stem Cell Niches of the Subventricular Zone
Azim Kasum, Hurtado-Chong Anahi, Fischer Bruno, Kumar Nitin, Zweifel Stefan, Taylor Verdon, Raineteau Olivier (2015), Transcriptional Hallmarks of Heterogeneous Neural Stem Cell Niches of the Subventricular Zone, in STEM CELLS, 33(7), 2232-2242.
miR379-410 cluster miRNAs regulate neurogenesis and neuronal migration by fine-tuning N-cadherin
Rago Luciano, Beattie Robert, Taylor Verdon, Winter Jennifer (2014), miR379-410 cluster miRNAs regulate neurogenesis and neuronal migration by fine-tuning N-cadherin, in EMBO JOURNAL, 33(8), 906-920.
Molecular Diversity Subdivides the Adult Forebrain Neural Stem Cell Population
Giachino Claudio, Basak Onur, Lugert Sebastian, Knuckles Philip, Obernier Kirsten, Fiorelli Roberto, Frank Stephan, Raineteau Olivier, Alvarez-Buylla Arturo, Taylor Verdon (2014), Molecular Diversity Subdivides the Adult Forebrain Neural Stem Cell Population, in STEM CELLS, 32(1), 70-84.
Neural Stem Cell of the Hippocampus: Development, Physiology Regulation, and Dysfunction in Disease
Rolando Chiara, Taylor Verdon (2014), Neural Stem Cell of the Hippocampus: Development, Physiology Regulation, and Dysfunction in Disease, in STEM CELLS IN DEVELOPMENT AND DISEASE, 107, 183-206.
Notching up neural stem cell homogeneity in homeostasis and disease
Giachino Claudio, Taylor Verdon (2014), Notching up neural stem cell homogeneity in homeostasis and disease, in FRONTIERS IN NEUROSCIENCE, 8, 32.
Endocardial to Myocardial Notch-Wnt-Bmp Axis Regulates Early Heart Valve Development
Wang Yidong, Wu Bingruo, Chamberlain Alyssa A., Lui Wendy, Koirala Pratistha, Susztak Katalin, Klein Diana, Taylor Verdon, Zhou Bin (2013), Endocardial to Myocardial Notch-Wnt-Bmp Axis Regulates Early Heart Valve Development, in PLOS ONE, 8(4), e60244.
GABA suppresses neurogenesis in the adult hippocampus through GABA(B) receptors
Giachino Claudio, Barz Michael, Tchorz Jan S., Tome Mercedes, Gassmann Martin, Bischofberger Josef, Bettler Bernhard, Taylor Verdon (2013), GABA suppresses neurogenesis in the adult hippocampus through GABA(B) receptors, in DEVELOPMENT, 141(1), 83-90.

Collaboration

Group / person Country
Types of collaboration
Dr. Mark Chong Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dan Littman United States of America (North America)
- 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
CNRS - Conférences Jacques Monod “Comparative biology of aging” Poster Regulation of multi-lineage potential of hippocampal stem cells by Drosha and Nuclear Factor I/B keeps oligodendrocytic differentiation in check 12.10.2015 Roscoff, France Rolando Chiara;
Notch meeting Talk given at a conference Differential roles of Notch1 and Notch2 signaling in the adult murine brain 04.10.2015 Athens, Greece Engler Anna;
University of Basel PhD Retreat Talk given at a conference Identification of a remnant niche in the adult brain 28.05.2015 Schwarzsee, Switzerland Engler Anna;
17th International Neuroscience Winter Conference Talk given at a conference Molecular determination of quiescence and binary cell fate choice in adult neural stem cells 07.04.2015 Soelden, Austria Taylor Verdon;
Gordon Conference "Glial Biology: Functional Interactions Among Glia & Neurons" Poster Drosha mediated posttranscriptional modifications regulate oligodendrocyte commitment in adult hippocampal neural stem cells 01.03.2015 Ventura, United States of America Rolando Chiara;
Swiss Neuroscience meeting Talk given at a conference Molecular regulation of mammalian neural stem cell diversity and differentiation 24.01.2015 Fribourg, Switzerland Taylor Verdon;
Neuroscience Institute Cavalieri Ottolenghi Talk given at a conference Non canonical Drosha pathway regulates hippocampal neural stem cell differentiation 28.11.2014 Orbassano, Italy Rolando Chiara;
University of Saarbrucken Individual talk Notch determination of quiescent and binary cell fate in adult neural stem cells 27.11.2014 Saarburcken, Germany Taylor Verdon;
Stem Cell Symposium Talk given at a conference Mechanisms of TDP-43 induced cell death during neural development 18.11.2014 Brescia, Italy Taylor Verdon;
Glioma Club London Talk given at a conference Tumour suppressor Notch signalling in glioma 19.10.2014 London, Great Britain and Northern Ireland Taylor Verdon;
Volkswagen Foundation DiSCUSS-CSCs Symposium Talk given at a conference Tumour suppressor Notch signalling in glioma 16.10.2014 Hannover, Germany Taylor Verdon;
SystemsX meeting Individual talk NeuroStemX: Systems analysis of mammalian forebrain development 15.10.2014 Zurich, Switzerland Taylor Verdon;
Notch meeting Talk given at a conference Notch determination of quiescent and binary cell fate in adult neural stem cells 28.09.2014 Athens, Greece Taylor Verdon;
Basel International Stem Cell Conference Poster Heterogeneity of adult murine hippocampal neurogenesis in physiological and pathological conditions 09.09.2014 Basel, Switzerland Engler Anna;
Basel International Stem Cell Conference Talk given at a conference Drosha mediated posttranscriptional modifications regulate fate commitment in mouse hippocampal Neural Stem Cells 09.09.2014 Basel, Switzerland Rolando Chiara;
ISSCR meeting Poster Drosha mediated posttranscriptional modifications regulate fate commitment in mouse hippocampal Neural Stem Cells 18.06.2014 Vancouver, Canada Rolando Chiara;
Neuroforum seminar Individual talk Notch signalling regulates adult neurogenesis from heterogeneous neural stem cell populations in the striatal ventricular wall 28.05.2014 Freiburg, Germany Taylor Verdon;
ISSCR Meeting Poster Modulation of Adult Hippocampal Neurogenesis in Physiological and Pathological Conditions 12.05.2014 Stockholm, Sweden Engler Anna;
Bench-to-Bedside meeting Talk given at a conference Mechanisms of TDP-43 induced cell death during neural development 07.02.2014 Basel, Switzerland Taylor Verdon;
BeNeFri Workshop Individual talk Molecular mechanisms of regulated neurogenesis 23.01.2014 Fribourg, Switzerland Taylor Verdon;
University of Basel PhD retreat Individual talk Analysis of neurogenesis in embryonic and adult mice: From Methods to Mechanisms 16.01.2014 Hasliberg, Switzerland Taylor Verdon;
University of Basel PhD retreat Poster Adult hippocampal neurogenesis - in good times and bad times 16.01.2014 Hasliberg, Switzerland Engler Anna;
European Glia Meeting Talk given at a conference Molecular and functional diversity in the adult forebrain neural stem cell population 03.07.2013 Berlin, Germany Taylor Verdon;
Neurogenesis Meeting Bordeaux Talk given at a conference Non-canonical stem cells in the aged and regenerating brain 24.06.2013 Bordeaux, France Taylor Verdon;
Roche Pharmaceuticals: Autism meeting Talk given at a conference Systems analysis of forebrain development-are there implications for autism? 07.06.2013 Basel, Switzerland Taylor Verdon;
Anne Rowling Clinic opening symposium Talk given at a conference Regulation of mammalian neurogenesis 27.05.2013 Edinburgh, Great Britain and Northern Ireland Taylor Verdon;
Roche Pharmaceuticals: Neuroscience meeting Individual talk Distinct neural stem cells population regulate homeostasis and regeneration 16.05.2013 Basel, Switzerland Taylor Verdon;
SystemsX meeting Individual talk NeuroStemX: Systems analysis of mammalian forebrain development 13.05.2013 Zurich, Switzerland Taylor Verdon;
15th International Neuroscience Winter Conference Talk given at a conference Heterogeneous neural stem cells in health and regeneration 09.04.2013 Soelden, Austria Taylor Verdon;
Helmholz Zentrum Munich Individual talk Heterogeneous active and quiescent adult neural stem cells in homeostasis and regeneration 04.04.2013 Munich, Germany Taylor Verdon;
Tokyo University Talk given at a conference Heterogeneous active and quiescent adult neural stem cells in homeostasis and regeneration 17.12.2012 Tokyo, Japan Taylor Verdon;
Japanese Biochemistry meeting Talk given at a conference Drosha regulates neurogenesis by controlling Neurogenin2 expression 13.12.2012 Fukuoka, Japan Taylor Verdon;
Japanese Swiss Developmental Biology Meeting Talk given at a conference Non-canonical functions of Drosha in regulating neurogenesis 04.12.2012 Kyoto, Japan Taylor Verdon;


Self-organised

Title Date Place
Basel International Stem Cell Conference 09.09.2014 Basel, Switzerland

Associated projects

Number Title Start Funding scheme
164085 Subcellular targeting microscopy - Signaling in Development and Oncology 01.06.2016 R'EQUIP
162609 Regulation of adult neural stem cell activity and fate downstream of Notch2 and Drosha 01.10.2015 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.
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