mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration.

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Tuberous Sclerosis Complex Gene Products, Tuberin and Hamartin, Control mTOR Signaling by Acting as a GTPase-Activating Protein Complex toward Rheb

Current Biology ◽

10.1016/s0960-9822(03)00506-2 ◽

2003 ◽

Vol 13 (15) ◽

pp. 1259-1268 ◽

Cited By ~ 754

Author(s):

Andrew R Tee ◽

Brendan D Manning ◽

Philippe P Roux ◽

Lewis C Cantley ◽

John Blenis

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Protein Complex ◽

Mtor Signaling ◽

Gene Products ◽

Gtpase Activating Protein

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Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells

The Journal of Cell Biology ◽

10.1083/jcb.201103018 ◽

2011 ◽

Vol 193 (4) ◽

pp. 695-710 ◽

Cited By ~ 60

Author(s):

Alla Amcheslavsky ◽

Naoto Ito ◽

Jin Jiang ◽

Y. Tony Ip

Keyword(s):

Stem Cells ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Critical Role ◽

Intestinal Stem Cells ◽

Stem Cell Markers ◽

Disc Cells ◽

Epithelial Structure ◽

Rates Of Growth ◽

Adult Drosophila

Intestinal stem cells (ISCs) in the adult Drosophila melanogaster midgut can respond to damage and support repair. We demonstrate in this paper that the tuberous sclerosis complex (TSC) plays a critical role in balancing ISC growth and division. Previous studies have shown that imaginal disc cells that are mutant for TSC have increased rates of growth and division. However, we report in this paper that loss of TSC in the adult Drosophila midgut results in the formation of much larger ISCs that have halted cell division. These mutant ISCs expressed proper stem cell markers, did not differentiate, and had defects in multiple steps of the cell cycle. Slowing the growth by feeding rapamycin or reducing Myc was sufficient to rescue the division defect. The TSC mutant guts had a thinner epithelial structure than wild-type tissues, and the mutant flies were more susceptible to tissue damage. Therefore, we have uncovered a context-dependent phenotype of TSC mutants in adult ISCs, such that the excessive growth leads to inhibition of division.

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Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy

Cell Stem Cell ◽

10.1016/j.stem.2016.07.019 ◽

2016 ◽

Vol 19 (5) ◽

pp. 663-671 ◽

Cited By ~ 236

Author(s):

Qiming Liang ◽

Zhifei Luo ◽

Jianxiong Zeng ◽

Weiqiang Chen ◽

Suan-Sin Foo ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Zika Virus ◽

Mtor Signaling

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Regulation of mast cell survival and function by tuberous sclerosis complex 1

Blood ◽

10.1182/blood-2011-05-353342 ◽

2012 ◽

Vol 119 (14) ◽

pp. 3306-3314 ◽

Cited By ~ 28

Author(s):

Jinwook Shin ◽

Hongjie Pan ◽

Xiao-Ping Zhong

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Survival ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Cell Activation ◽

Cytokine Production ◽

Mast Cell Degranulation ◽

Mtor Signaling ◽

Mast Cell Activation

Abstract Mast cells play critical roles in allergic disorders and asthma. The importance of tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown. Here, we report that TSC1 is a critical regulator for mTOR signaling in mast cells downstream of FcεRI and c-Kit, and differentially controls mast cell degranulation and cytokine production. TSC1-deficiency results in impaired mast cell degranulation, but enhanced cytokine production in vitro and in vivo after FcεRI engagement. Furthermore, TSC1 is critical for mast cell survival through multiple pathways of apoptosis including the down-regulation of p53, miR-34a, reactive oxygen species, and the up-regulation of Bcl-2. Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast cell-mediated diseases.

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