scholarly journals Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain

2011 ◽  
Vol 208 (5) ◽  
pp. 937-948 ◽  
Author(s):  
Benedetta Artegiani ◽  
Dirk Lindemann ◽  
Federico Calegari
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Adult Neurogenesis ◽  
Adult Mouse ◽  
Physiological Role ◽  
Mammalian Brain ◽  
Temporal Control ◽  
Somatic Stem Cells

Neural stem cells (NSCs) in the adult mammalian brain generate neurons and glia throughout life. However, the physiological role of adult neurogenesis and the use of NSCs for therapy are highly controversial. One factor hampering the study and manipulation of neurogenesis is that NSCs, like most adult somatic stem cells, are difficult to expand and their switch to differentiation is hard to control. In this study, we show that acute overexpression of the cdk4 (cyclin-dependent kinase 4)–cyclinD1 complex in the adult mouse hippocampus cell-autonomously increases the expansion of neural stem and progenitor cells while inhibiting neurogenesis. Importantly, we developed a system that allows the temporal control of cdk4–cyclinD1 overexpression, which can be used to increase the number of neurons generated from the pool of manipulated precursor cells. Beside providing a proof of principle that expansion versus differentiation of somatic stem cells can be controlled in vivo, our study describes, to the best of our knowledge, the first acute and inducible temporal control of neurogenesis in the mammalian brain, which may be critical for identifying the role of adult neurogenesis, using NSCs for therapy, and, perhaps, extending our findings to other adult somatic stem cells.

scholarly journals The Microtubule Severing Protein Katanin Regulates Proliferation of Neuronal Progenitors in Embryonic and Adult Neurogenesis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Franco L. Lombino ◽  
Mary Muhia ◽  
Jeffrey Lopez-Rojas ◽  
Monika S. Brill ◽  
Edda Thies ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Critical Role ◽  
Mammalian Brain ◽  
Cellular Functions ◽  
Microtubule Severing ◽  
Neuronal Progenitor ◽  
Neuronal Progenitors ◽  
Adult Hippocampus

Abstract Microtubule severing regulates cytoskeletal rearrangement underlying various cellular functions. Katanin, a heterodimer, consisting of catalytic (p60) and regulatory (p80) subunits severs dynamic microtubules to modulate several stages of cell division. The role of p60 katanin in the mammalian brain with respect to embryonic and adult neurogenesis is poorly understood. Here, we generated a Katna1 knockout mouse and found that consistent with a critical role of katanin in mitosis, constitutive homozygous Katna1 depletion is lethal. Katanin p60 haploinsufficiency induced an accumulation of neuronal progenitors in the subventricular zone during corticogenesis, and impaired their proliferation in the adult hippocampus dentate gyrus (DG) subgranular zone. This did not compromise DG plasticity or spatial and contextual learning and memory tasks employed in our study, consistent with the interpretation that adult neurogenesis may be associated with selective forms of hippocampal-dependent cognitive processes. Our data identify a critical role for the microtubule-severing protein katanin p60 in regulating neuronal progenitor proliferation in vivo during embryonic development and adult neurogenesis.

scholarly journals Evolutionarily Conserved Role of Nucleostemin: Controlling Proliferation of Stem/Progenitor Cells during Early Vertebrate Development

2006 ◽  
Vol 26 (24) ◽  
pp. 9291-9301 ◽  
Author(s):  
Chantal Beekman ◽  
Massimo Nichane ◽  
Sarah De Clercq ◽  
Marion Maetens ◽  
Thomas Floss ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Embryonic Stem Cells ◽  
Progenitor Cells ◽  
Control Cell ◽  
Embryonic Stem ◽  
Physiological Role ◽  
Specific Gene

ABSTRACT Nucleostemin (NS) is a putative GTPase expressed preferentially in the nucleoli of neuronal and embryonic stem cells and several cancer cell lines. Transfection and knockdown studies indicated that NS controls the proliferation of these cells by interacting with the p53 tumor suppressor protein and regulating its activity. To assess the physiological role of NS in vivo, we generated a mutant mouse line with a specific gene trap event that inactivates the NS allele. The corresponding NS −/− embryos died around embryonic day 4. Analyses of NS mutant blastocysts indicated that NS is not required to maintain pluripotency, nucleolar integrity, or survival of the embryonic stem cells. However, the homozygous mutant blastocysts failed to enter S phase even in the absence of functional p53. Haploid insufficiency of NS in mouse embryonic fibroblasts leads to decreased cell proliferation. NS also functions in early amphibian development to control cell proliferation of neural progenitor cells. Our results show that NS has a unique ability, derived from an ancestral function, to control the proliferation rate of stem/progenitor cells in vivo independently of p53.

scholarly journals In vitro and in vivo CRISPR-Cas9 screens reveal drivers of aging in neural stem cells of the brain

2021 ◽  
Author(s):  
Tyson J Ruetz ◽  
Chloe M Kashiwagi ◽  
Bhek Morton ◽  
Robin W Yeo ◽  
Dena S Leeman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Primary Cultures ◽  
Mammalian Brain ◽  
Aging Brain ◽  
Gene Knockouts ◽  
Old Mice

Aging impairs the ability of neural stem cells to transition from quiescence to activation (proliferation) in the adult mammalian brain. Neural stem cell (NSC) functional decline results in decreased production of new neurons and defective regeneration upon injury during aging, and this is exacerbated in Alzheimer's disease. Many genes are upregulated with age in NSCs, and the knockout of some of these boosts old NSC activation and rejuvenates aspects of old brain function. But systematic functional testing of genes in old NSCs - and more generally in old cells - has not been done. This has been a major limiting factor in identifying the most promising rejuvenation interventions. Here we develop in vitro and in vivo high-throughput CRISPR-Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screening pipeline in primary cultures of young and old NSCs identifies over 300 gene knockouts that specifically restore old NSC activation. Interestingly, the top gene knockouts are involved in glucose import, cilium organization and ribonucleoprotein structures. To determine which gene knockouts have a rejuvenating effect for the aging brain, we establish a scalable CRISPR-Cas9 screening platform in vivo in old mice. Of the 50 gene knockouts we tested in vivo, 23 boost old NSC activation and production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes for the GLUT4 glucose transporter, is a top rejuvenating intervention for old NSCs. GLUT4 protein expression increases in the stem cell niche during aging, and we show that old NSCs indeed uptake ~2-fold more glucose than their young counterparts. Transient glucose starvation increases the ability of old NSCs to activate, which is not further improved by knockout of Slc2a4/GLUT4. Together, these results indicate that a shift in glucose uptake contributes to the decline in NSC activation with age, but that it can be reversed by genetic or external interventions. Importantly, our work provides scalable platforms to systematically identify genetic interventions that boost old NSC function, including in vivo in old brains, with important implications for regenerative and cognitive decline during aging.

scholarly journals Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice

2011 ◽  
Vol 193 (1) ◽  
pp. 31-39 ◽  
Author(s):  
Shinichi Nakagawa ◽  
Takao Naganuma ◽  
Go Shioi ◽  
Tetsuro Hirose
Keyword(s):  
Adult Mouse ◽  
Expression Patterns ◽  
Physiological Role ◽  
Growth Conditions ◽  
Nuclear Bodies ◽  
Cellular Functions ◽  
Mouse Tissues

Nuclei of higher organisms are well structured and have multiple, distinct nuclear compartments or nuclear bodies. Paraspeckles are recently identified mammal-specific nuclear bodies ubiquitously found in most cells cultured in vitro. To investigate the physiological role of paraspeckles, we examined the in vivo expression patterns of two long noncoding RNAs, NEAT1_1 and NEAT1_2, which are essential for the architectural integrity of nuclear bodies. Unexpectedly, these genes were only strongly expressed in a particular subpopulation of cells in adult mouse tissues, and prominent paraspeckle formation was observed only in the cells highly expressing NEAT1_2. To further investigate the cellular functions of paraspeckles, we created an animal model lacking NEAT1 by gene targeting. These knockout mice were viable and fertile under laboratory growth conditions, showing no apparent phenotypes except for the disappearance of paraspeckles. We propose that paraspeckles are nonessential, subpopulation-specific nuclear bodies formed secondary to particular environmental triggers.

scholarly journals GLI3 Is Required for OLIG2+ Progeny Production in Adult Dorsal Neural Stem Cells

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 218
Author(s):  
Rebecca J. Embalabala ◽  
Asa A. Brockman ◽  
Amanda R. Jurewicz ◽  
Jennifer A. Kong ◽  
Kaitlyn Ryan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Large Population ◽  
Shh Pathway ◽  
Positional Identity ◽  
Olfactory Interneurons

The ventricular–subventricular zone (V-SVZ) is a postnatal germinal niche. It holds a large population of neural stem cells (NSCs) that generate neurons and oligodendrocytes for the olfactory bulb and (primarily) the corpus callosum, respectively. These NSCs are heterogeneous and generate different types of neurons depending on their location. Positional identity among NSCs is thought to be controlled in part by intrinsic pathways. However, extrinsic cell signaling through the secreted ligand Sonic hedgehog (Shh) is essential for neurogenesis in both the dorsal and ventral V-SVZ. Here we used a genetic approach to investigate the role of the transcription factors GLI2 and GLI3 in the proliferation and cell fate of dorsal and ventral V-SVZ NSCs. We find that while GLI3 is expressed in stem cell cultures from both dorsal and ventral V-SVZ, the repressor form of GLI3 is more abundant in dorsal V-SVZ. Despite this high dorsal expression and the requirement for other Shh pathway members, GLI3 loss affects the generation of ventrally-, but not dorsally-derived olfactory interneurons in vivo and does not affect trilineage differentiation in vitro. However, loss of GLI3 in the adult dorsal V-SVZ in vivo results in decreased numbers of OLIG2-expressing progeny, indicating a role in gliogenesis.

scholarly journals In Vivo Targeted Magnetic Resonance Imaging of Endogenous Neural Stem Cells in the Adult Rodent Brain

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Xiao-Mei Zhong ◽  
Fang Zhang ◽  
Ming Yang ◽  
Xue-Hua Wen ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mr Imaging ◽  
Neural Stem Cells ◽  
Molecular Probe ◽  
Mammalian Brain ◽  
Intraventricular Administration ◽  
In Vivo Monitoring ◽  
Rodent Brain ◽  
Endogenous Neural Stem Cells

Neural stem cells in the adult mammalian brain have a significant level of neurogenesis plasticity. In vivo monitoring of adult endogenous NSCs would be of great benefit to the understanding of the neurogenesis plasticity under normal and pathological conditions. Here we show the feasibility of in vivo targeted MR imaging of endogenous NSCs in adult mouse brain by intraventricular delivery of monoclonal anti-CD15 antibody conjugated superparamagnetic iron oxide nanoparticles. After intraventricular administration of these nanoparticles, the subpopulation of NSCs in the anterior subventricular zone and the beginning of the rostral migratory stream could be in situ labeled and were in vivo visualized with 7.0-T MR imaging during a period from 1 day to 7 days after the injection. Histology confirmed that the injected targeted nanoparticles were specifically bound to CD15 positive cells and their surrounding extracellular matrix. Our results suggest that in vivo targeted MR imaging of endogenous neural stem cells in adult rodent brain could be achieved by using anti-CD15-SPIONs as the molecular probe; and this targeting imaging strategy has the advantage of a rapid in vivo monitoring of the subpopulation of endogenous NSCs in adult brains.

Hypothalamic regulation of regionally distinct adult neural stem cells and neurogenesis

Science ◽  
2017 ◽  
Vol 356 (6345) ◽  
pp. 1383-1386 ◽  
Author(s):  
Alex Paul ◽  
Zayna Chaker ◽  
Fiona Doetsch
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Adult Mouse ◽  
Brain Area ◽  
Regional Identity ◽  
Mammalian Brain ◽  
Granule Neurons ◽  
Environmental Signals ◽  
Hypothalamic Regulation ◽  
Adult Mammalian Brain

Neural stem cells (NSCs) in specialized niches in the adult mammalian brain generate neurons throughout life. NSCs in the adult mouse ventricular-subventricular zone (V-SVZ) exhibit a regional identity and, depending on their location, generate distinct olfactory bulb interneuron subtypes. Here, we show that the hypothalamus, a brain area regulating physiological states, provides long-range regionalized input to the V-SVZ niche and can regulate specific NSC subpopulations. Hypothalamic proopiomelanocortin neurons selectively innervate the anterior ventral V-SVZ and promote the proliferation of Nkx2.1+ NSCs and the generation of deep granule neurons. Accordingly, hunger and satiety regulate adult neurogenesis by modulating the activity of this hypothalamic–V-SVZ connection. Our findings reveal that neural circuitry, via mosaic innervation of the V-SVZ, can recruit distinct NSC pools, allowing on-demand neurogenesis in response to physiology and environmental signals.

Preferential Transfection of Adult Mouse Neural Stem Cells and Their Immediate Progeny in Vivo with Polyethylenimine

2002 ◽  
Vol 19 (2) ◽  
pp. 165-174 ◽  
Author(s):  
Gregory F. Lemkine ◽  
Stefano Mantero ◽  
Carole Migné ◽  
Aicha Raji ◽  
Daniel Goula ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Adult Mouse

In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain

Development ◽  
1998 ◽  
Vol 125 (12) ◽  
pp. 2251-2261 ◽  
Author(s):  
C.M. Morshead ◽  
C.G. Craig ◽  
D. van der Kooy
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Olfactory Bulb ◽  
Neural Stem Cells ◽  
Anterior Commissure ◽  
Mammalian Brain ◽  
Proliferating Cells ◽  
Asymmetric Mode ◽  
Clone Size

The adult mammalian forebrain contains a population of multipotential neural stem cells in the subependyma of the lateral ventricles whose progeny are the constitutively proliferating cells, which divide actively throughout life. The adult mammalian brain is ideal for examining the kinetics of the stem cells due to their strict spatial localization and the limited and discrete type of progeny generated (constitutively proliferating cells). Clonal lineage analyses 6 days after retrovirus infection revealed that under baseline conditions 60% of the constitutively proliferating cells undergo cell death, 25% migrate to the olfactory bulb and 15% remain confined to the lateral ventricle subependyma (where they reside for approximately 15 days). Analysis of single cell clones 31 days after retroviral infection revealed that the stem cell divides asymmetrically to self-renew and give rise to constitutively proliferating cells. Following repopulation of the depleted subependyma the average clone size is 2.8 times larger than control, yet the absolute number of cells migrating to the olfactory bulb is maintained and the stem cell retains its asymmetric mode of division. The number of neural stem cells in the adult forebrain 33 days after repopulation of the subependyma was estimated using bromodeoxyuridine labeling of subepenydmal cells. There were calculated to be 1200–1300 cells between the rostral corpus callosum and rostral anterior commissure; these data support a lineage model similar to those based on stem cell behavior in other tissue types.

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