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See detailA systemic transcriptome analysis reveals the regulation of neural stem cell maintenance by an E2F1-miRNA feedback loop.
Palm, Thomas; Hemmer, Kathrin; Winter, Julia et al

in Nucleic Acids Research (2013), 41(6), 3699-712

Stem cell fate decisions are controlled by a molecular network in which transcription factors and miRNAs are of key importance. To systemically investigate their impact on neural stem cell (NSC ... [more ▼]

Stem cell fate decisions are controlled by a molecular network in which transcription factors and miRNAs are of key importance. To systemically investigate their impact on neural stem cell (NSC) maintenance and neuronal commitment, we performed a high-throughput mRNA and miRNA profiling and isolated functional interaction networks of involved mechanisms. Thereby, we identified an E2F1-miRNA feedback loop as important regulator of NSC fate decisions. Although E2F1 supports NSC proliferation and represses transcription of miRNAs from the miR-17 approximately 92 and miR-106a approximately 363 clusters, these miRNAs are transiently up-regulated at early stages of neuronal differentiation. In these early committed cells, increased miRNAs expression levels directly repress E2F1 mRNA levels and inhibit cellular proliferation. In mice, we demonstrated that these miRNAs are expressed in the neurogenic areas and that E2F1 inhibition represses NSC proliferation. The here presented data suggest a novel interaction mechanism between E2F1 and miR-17 approximately 92 / miR-106a approximately 363 miRNAs in controlling NSC proliferation and neuronal differentiation. [less ▲]

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See detailTRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation
Hillje, Anna-Lena UL; Pavlou, Maria Angeliki UL; Beckmann, Elisabeth et al

in Cell Death & Disease (2013)

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See detailThe Parkinson's Disease-Associated LRRK2 Mutation R1441G Inhibits Neuronal Differentiation of Neural Stem Cells.
Bahnassawy, Lamia A; Nicklas, Sarah; Palm, Thomas et al

in Stem Cells & Development (2013)

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause familial as well as sporadic Parkinson's disease (PD) that is characterized by an age-dependent degeneration of dopaminergic neurons. LRRK2 ... [more ▼]

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause familial as well as sporadic Parkinson's disease (PD) that is characterized by an age-dependent degeneration of dopaminergic neurons. LRRK2 is strongly expressed in neural stem cells (NSCs), but still the exact molecular function of LRRK2 in these cells remains unknown. By performing a systemic analysis of the gene expression profile of LRRK2-deficient NSCs, we found that the expression of several PD-associated genes, such as oxidation and reduction in mitochondria, are deregulated on LRRK2 absence. Our data, indeed, indicate that LRRK2 regulates the level of cellular oxidative stress and thereby influences the survival of NSCs. Furthermore, the lack of LRRK2 leads to an up-regulation of neuronal differentiation-inducing processes, including the Let-7a pathway. On the other hand, the constitutive mutant of LRRK2(R1441G), known to cause PD, leads to down-regulation of the same pathway. In agreement with the function of Let-7a during neuronal differentiation, LRRK2-deficient NSCs differentiate faster than wild-type cells, while LRRK2(R1441G)-expressing NSCs show impaired neuronal differentiation. These results might help better characterize the molecular mechanisms underlying the role of LRRK2 in NSCs and would further improve potential cell-replacement strategies as well as drug discovery approaches. [less ▲]

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See detailMiRNAs and neural stem cells: a team to treat Parkinson's disease?
Palm, Thomas; Bahnassawy, Lamia A; Schwamborn, Jens Christian UL

in RNA Biology (2012), 9(6), 720-30

Parkinson's disease (PD) is a common neurodegenerative disorder with no proven neuroprotective or neurorestorative therapies. During disease progression, degeneration of dopaminergic neurons of the ... [more ▼]

Parkinson's disease (PD) is a common neurodegenerative disorder with no proven neuroprotective or neurorestorative therapies. During disease progression, degeneration of dopaminergic neurons of the central nervous system occurs. Therefore, therapies that either aim on the inhibition of this degeneration or on the replacement of the degenerated neurons are needed. On the one hand, arrest of degeneration might be achievable through specific inhibition of disease associated genes like alpha-Synuclein or Leucine rich repeat kinase 2 (LRRK2). On the other hand, based on neural stem cells that bear the ability to generate new dopaminergic neurons, replacement of degenerated cells could be accomplished. Since both approaches can be regulated by micro-RNAs, these molecules have an enormous therapeutic potential. In this review, we will focus on the neurobiological and neurodegenerative implications of miRNAs and highlight their role in stem cell fate decisions. Finally, we will discuss their potential as therapeutic agents and targets for Parkinson's disease. [less ▲]

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See detailJAM-C is an apical surface marker for neural stem cells.
Stelzer, Sandra; Worlitzer, Maik M. A.; Bahnassawy, Lamia A et al

in Stem Cells & Development (2012), 21(5), 757-66

Junctional adhesion molecule-C (JAM-C) is an adhesive cell surface protein expressed in various cell types. JAM-C localizes to the apically localized tight junctions (TJs) between contacting endothelial ... [more ▼]

Junctional adhesion molecule-C (JAM-C) is an adhesive cell surface protein expressed in various cell types. JAM-C localizes to the apically localized tight junctions (TJs) between contacting endothelial and epithelial cells, where it contributes to cell-cell adhesions. Just as those epithelial cells, also neural stem cells are highly polarized along their apical-basal axis. The defining feature of all stem cells, including neural stem cells (NSCs) is their ability to self renew. This self-renewal depends on the tight control of symmetric and asymmetric cell divisions. In NSCs, the decision whether a division is symmetric or asymmetric largely depends on the distribution of the apical membrane and cell fate determinants on the basal pole of the cell. In this study we demonstrate that JAM-C is expressed on neural progenitor cells and neural stem cells in the embryonic as well as the adult mouse brain. Furthermore, we demonstrate that in vivo JAM-C shows enrichment at the apical surface and therefore is asymmetrically distributed during cell divisions. These results define JAM-C as a novel surface marker for neural stem cells. [less ▲]

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See detailNeural stem cells maintain their stemness through protein kinase C zeta-mediated inhibition of TRIM32.
Hillje, Anna-Lena; Worlitzer, Maik M. A.; Palm, Thomas et al

in Stem Cells (2011), 29(9), 1437-47

Several studies over the last couple of years have delivered insights into the mechanisms that drive neuronal differentiation. However, the mechanisms that ensure the maintenance of stemness ... [more ▼]

Several studies over the last couple of years have delivered insights into the mechanisms that drive neuronal differentiation. However, the mechanisms that ensure the maintenance of stemness characteristics in neural stem cells over several rounds of cell divisions are still largely unknown. Here, we provide evidence that the neuronal fate determinant TRIM32 binds to the protein kinase C zeta. Through this interaction, TRIM32 is retained in the cytoplasm. However, during differentiation, this interaction is abrogated and TRIM32 translocates to the nucleus to initiate neuronal differentiation by targeting c-Myc for proteasomal degradation. [less ▲]

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See detailBrain tumor stem cells.
Palm, Thomas; Schwamborn, Jens Christian UL

in Biological Chemistry (2010), 391(6), 607-17

Since the end of the 'no-new-neuron' theory, emerging evidence from multiple studies has supported the existence of stem cells in neurogenic areas of the adult brain. Along with this discovery, neural ... [more ▼]

Since the end of the 'no-new-neuron' theory, emerging evidence from multiple studies has supported the existence of stem cells in neurogenic areas of the adult brain. Along with this discovery, neural stem cells became candidate cells being at the origin of brain tumors. In fact, it has been demonstrated that molecular mechanisms controlling self-renewal and differentiation are shared between brain tumor stem cells and neural stem cells and that corruption of genes implicated in these pathways can direct tumor growth. In this regard, future anticancer approaches could be inspired by uncovering such redundancies and setting up treatments leading to exhaustion of the cancer stem cell pool. However, deleterious effects on (normal) neural stem cells should be minimized. Such therapeutic models underline the importance to study the cellular mechanisms implicated in fate decisions of neural stem cells and the oncogenic derivation of adult brain cells. In this review, we discuss the putative origins of brain tumor stem cells and their possible implications on future therapies. [less ▲]

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