Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis

Ehret, Fanny; Vogler, Steffen; Pojar, Sherin; Elliott, David A.; Bradke, Frank; Steiner, Barbara; Kempermann, Gerd

doi:10.1016/j.nbd.2014.12.018

Cited by 25 publications

(35 citation statements)

References 46 publications

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“…The decreased neurogenesis in Notch3 overexpressing mice of the long-term group replicates the finding of our previous study in six-months-old TgN3 WT mice22. The fact that the decreased neurogenesis already observed four weeks after BrdU cell labeling22 is still evident after five more months, shows that this is really due to a suppression of cell proliferation by Notch3 overexpression, as suggested in our previous work, rather than an influence on cell survival.…”

Section: Discussionsupporting

confidence: 90%

“…The fact that the decreased neurogenesis already observed four weeks after BrdU cell labeling22 is still evident after five more months, shows that this is really due to a suppression of cell proliferation by Notch3 overexpression, as suggested in our previous work, rather than an influence on cell survival. Notch3 and Notch1 are possibly co-expressed in proliferating hippocampal precursor cells22. Moreover, Notch1 has been shown to be essential for progenitor pool maintenance and regulation of proliferation161830.…”

Section: Discussionsupporting

confidence: 69%

“…This suggests that although neurogenesis is not yet reduced in younger TgN3 WT mice, it is already disturbed due to Notch3 overexpression as it could not be stimulated by RUN and ENR. In support of this, we have demonstrated in our previous work using a KCl-activation neurosphere assay that the proliferative activity of neural precursor cells was potentially reduced by Notch3 overexpression22. This might have prevented the activation by RUN or ENR.…”

Section: Discussionsupporting

confidence: 59%

“…Aside from the direct effect Notch3 can exert on neurogenesis by its expression in neural precursor cells, the Notch3-dependent vascular influence might, in turn, also be responsible for the observed cognitive impairments in CADASIL patients. Our previous study using a mouse model overexpressing Notch3 with a CADASIL mutation has demonstrated that adult hippocampal neurogenesis is indeed affected22. We have shown that neural cell proliferation and survival are reduced in the CADASIL mice at 12 months of age.…”

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confidence: 77%

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Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model

Klein

Schreyer

Kohrs

et al. 2017

Sci Rep

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In the course of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a dysregulated adult hippocampal neurogenesis has been suggested as a potential mechanism for early cognitive decline. Previous work has shown that mice overexpressing wild type Notch3 and mice overexpressing Notch3 with a CADASIL mutation display impaired cell proliferation and survival of newly born hippocampal neurons prior to vascular abnormalities. Here, we aimed to elucidate how the long-term survival of these newly generated neurons is regulated by Notch3. Knowing that adult neurogenesis can be robustly stimulated by physical exercise and environmental enrichment, we also investigated the influence of such stimuli as potential therapeutic instruments for a dysregulated hippocampal neurogenesis in the CADASIL mouse model. Therefore, young-adult female mice were housed in standard (STD), environmentally enriched (ENR) or running wheel cages (RUN) for either 28 days or 6 months. Mice overexpressing mutated Notch3 and developing CADASIL (TgN3R169C), and mice overexpressing wild type Notch3 (TgN3WT) were used. We found that neurogenic stimulation by RUN and ENR is apparently impaired in both transgenic lines. The finding suggests that a disturbed neurogenic process due to Notch3-dependent micromilieu changes might be one vascular-independent mechanism contributing to cognitive decline observed in CADASIL.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 69%

Section: Discussionsupporting

confidence: 59%

mentioning

confidence: 77%

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Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model

Klein

Schreyer

Kohrs

et al. 2017

Sci Rep

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“…Besides these cells, the niche also contains nestin-negative progenitor cells (type-3), microglia and granule cell neurons. There are only capillaries in the SGZ, so no vascular smooth muscle cells are found (Ehret et al, 2015) but current isolation protocols for pericytes do not yet distinguish between these populations.…”

Section: The Hippocampal Niche In Vivomentioning

confidence: 99%

A co-culture model of the hippocampal neurogenic niche reveals differential effects of astrocytes, endothelial cells and pericytes on proliferation and differentiation of adult murine precursor cells

2015

Self Cite

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The niche concept of stem cell biology proposes a functional unit between the precursor cells and their local microenvironment, to which several cell types might contribute by cell-cell contacts, extracellular matrix, and humoral factors. We here established three co-culture models (with cell types separated by membrane) for both adherent monolayers and neurospheres to address the potential influence of different niche cell types in the neurogenic zone of the adult hippocampus of mice. Astrocytes and endothelial cells enhanced precursor cell proliferation and neurosphere formation. Endothelial factors also led to a prolonged increase in proliferation after growth factor withdrawal, which otherwise induces differentiation. All niche cell types enhanced cell survival in monolayer cultures, endothelial cells also stimulated neuronal differentiation. A parallel trend elicited by astrocytes did not reach conventional statistical significance. Pericytes had variable effects here. We did not observe changes in differentiation in neurosphere co-cultures. In summary, our data indicate that in precursor cell culture protocols survival could be improved by adding as yet unknown factors physiologically contributed by astrocytes and endothelial cells. Our findings also underscore the complexity of the niche and the differential impact of factors from the different sources on distinct aspects of neuronal development. With the help of the models presented here, identification of these factors and their specific biological activity can now be initiated.

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The Notch pathway in CNS homeostasis and neurodegeneration

Artavanis‐Tsakonas

Louvi

2019

WIREs Developmental Biology

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The role of the Notch signaling pathway in neural development has been well established over many years. More recent studies, however, have demonstrated that Notch continues to be expressed and active throughout adulthood in many areas of the central nervous system. Notch signals have been implicated in adult neurogenesis, memory formation, and synaptic plasticity in the adult organism, as well as linked to acute brain trauma and chronic neurodegenerative conditions. NOTCH3 mutations are responsible for the most common form of hereditary stroke, the progressive disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Notch has also been associated with several progressive neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Although numerous studies link Notch activity with CNS homeostasis and neurodegenerative diseases, the data thus far are primarily correlative, rather than functional. Nevertheless, the evidence for Notch pathway activity in specific neural cellular contexts is strong, and certainly intriguing, and points to the possibility that the pathway carries therapeutic promise. This article is categorized under: Nervous System Development > Flies Signaling Pathways > Cell Fate Signaling Nervous System Development > Vertebrates: General Principles

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Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis

Cited by 25 publications

References 46 publications

Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model

Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model

A co-culture model of the hippocampal neurogenic niche reveals differential effects of astrocytes, endothelial cells and pericytes on proliferation and differentiation of adult murine precursor cells

The Notch pathway in CNS homeostasis and neurodegeneration

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