The critical role of cyclin D2 in adult neurogenesis

Kowalczyk, Anna; Filipkowski, Robert K.; Rylski, Marcin; Wilczyński, Grzegorz M.; Konopacki, Filip A.; Jaworski, Jacek; Ciemerych, Maria A.; Siciński, Piotr; Kaczmarek, Leszek

doi:10.1083/jcb.200404181

Cited by 165 publications

(207 citation statements)

References 31 publications

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“…This contrasts with the effects of other molecular mechanisms, such as cyclin D2, found to be required for virtually the entire basal hippocampal neurogenesis observed in mice. 38 Importantly, our study also suggests that MIF is required for the stimulation of hippocampal cell proliferation by antidepressants (at least by the SSRI fluoxetine), highlighting MIF as a potential important molecular target to develop novel neurogenesis-related antidepressant treatments.…”

Section: Discussionmentioning

confidence: 91%

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

et al. 2010

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Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety-and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

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Section: Discussionmentioning

confidence: 91%

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

et al. 2010

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“…The tumor-suppressing capacity of endogenous NPCs may explain, why glioma growth is attenuated in younger animals and why younger mice outlive older animals after glioblastoma inoculation into the brain. Adult neurogenesis, describing the presence, proliferation, and differentiation of stem and precursor cells in the adult brain, declines with aging (Kowalczyk et al, 2004;Tropepe et al, 1997). Consequentially, experimental glioblastomas attract large numbers of NPCs only in the young brain, while this effect is strongly reduced in the older brain (Walzlein et al, 2008).…”

Section: The Interaction Of Glioblastomas With Neural Precursor Cellsmentioning

confidence: 99%

The brain tumor microenvironment

Charles

Holland

Gilbertson

et al. 2011

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High-grade brain tumors are heterogeneous with respect to the composition of bona fide tumor cells and with respect to a range of intermingling parenchymal cells. Glioblastomas harbor multiple cell types, some with increased tumorigenicity and stem cell-like capacity. The stem-like cells may be the cells of origin for tumor relapse. However, the tumor-associated parenchymal cells such as vascular cells, microglia, peripheral immune cells, and neural precursor cells also play a vital role in controlling the course of pathology. In this review, we describe the multiple interactions of bulk glioma cells and glioma stem cells with parenchymal cell populations and highlight the pathological impact as well as signaling pathways known for these types of cell-cell communication. The tumor-vasculature not only nourishes glioblastomas, but also provides a specialized niche for these stem-like cells. In addition, microglial cells, which can contribute up to 30% of a brain tumor mass, play a role in glioblastoma cell invasion. Moreover, non-neoplastic astrocytes can be converted into a reactive phenotype by the glioma microenvironment and can then secrete a number of factors which influences tumor biology. The young brain may have the capacity to inhibit gliomagenesis by the endogenous neural precursor cells, which secrete tumor suppressive factors. The factors, pathways, and interactions described in this review provide a new prospective on the cell biology of primary brain tumors, which may ultimately generate new treatment modalities. However, our picture of the multiple interactions between parenchymal and tumor cells is still incomplete. V

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“…For instance, p27 Kip1 selectively constrains transit-amplifying cell proliferation in the SVZ [7], whereas deletion of Cyclin D2 virtually abrogates adult neurogenesis [8]. However, the direct and specific contribution of the catalytic partners Cdk4 and Cdk6 to adult neurogenesis has not been evaluated yet.…”

Section: Introductionmentioning

confidence: 99%

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

et al. 2011

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The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G 1 regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G 1 length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM CELLS 2011;29:713-724 Disclosure of potential conflicts of interest is found at the end of this article.

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The critical role of cyclin D2 in adult neurogenesis

Cited by 165 publications

References 31 publications

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

The brain tumor microenvironment

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

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