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See detailThe neural stem cell fate determinant TRIM32 regulates complex behavioral traits
Hillje, Anna-Lena UL; Beckmann, Elisabeth; Pavlou, Maria Angeliki UL et al

in Frontiers in Cellular Neuroscience (2015)

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See detailTRIM32 Senses and Restricts Influenza A Virus by Ubiquitination of PB1 Polymerase
Bishi; Wang, Lingyan; Ding, Hao et al

in PLoS Pathogens (2015)

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See detailTRIM32 modulates pluripotency entry and exit by directly regulating Oct4 stability
Bahnassawy, Lamia’a; Perumal, Thanneer; Gonzalez Cano, Laura UL et al

in Scientific Reports (2015)

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See detailDifferentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture
Lucumi Moreno, Edinson UL; Hachi, Siham UL; Hemmer, Kathrin UL et al

in Lab on a Chip - Miniaturisation for Chemistry and Biology (2015), 15

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See detailInduced Neural Stem Cells Achieve Long-Term Survival and Functional Integration in the Adult Mouse Brain
Hemmer, Kathrin UL; Zhang, Mingyue; van Wuellen, Thea et al

in Stem Cell Reports (2014)

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See detailOrigin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain
Hargus, Gunnar; Ehrlicher, Marc; Arauzo-Bravo, Marcos et al

in Cell Reports (2014)

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See detailThe majority of newly generated cells in the adult mouse substantia nigra express low levels of Doublecortin, but their proliferation is unaffected by 6-OHDA-induced nigral lesion or Minocycline-mediated inhibition of neuroinflammation.
Worlitzer, Maik M. A.; Viel, Thomas; Jacobs, Andreas H. et al

in European Journal of Neuroscience (2013)

Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). However, whether regenerative endogenous neurogenesis is taking place in the mammalian SN of ... [more ▼]

Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). However, whether regenerative endogenous neurogenesis is taking place in the mammalian SN of parkinsonian and non-parkinsonian brains remains of debate. Here, we tested whether proliferating cells in the SN and their neurogenic potential would be affected by anti-inflammatory treatment under physiological conditions and in the 6-hydroxy-dopamine (6-OHDA) Parkinson's disease mouse model. We report that the majority of newly generated nigral cells are positive for Doublecortin (Dcx), which is an often used marker for neural progenitor cells. Yet, Dcx expression levels in these cells were much lower than in neural progenitor cells of the subventricular zone and the dentate gyrus neural progenitor cells. Furthermore, these newly generated nigral cells are negative for neuronal lineage markers such as TuJ1 and NeuN. Therefore, their neuronal commitment is questionable. Instead, we found evidence for oligodendrogenesis and astrogliosis in the SN. Finally, neither short-term nor long-term inhibition of neuroinflammation by Minocycline- or 6-OHDA-induced lesion affected the numbers of newly generated cells in our disease paradigm. Our findings of adult generated Dcx+ cells in the SN add important data for understanding the cellular composition and consequently the regenerative capacity of the SN. [less ▲]

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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 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 and Disease (2013)

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See detailRegulatory feedback loop between TP73 and TRIM32.
Gonzalez-Cano, L.; Hillje, Anna-Lena UL; Fuertes-Alvarez, S. et al

in Cell Death and Disease (2013), 4

The p73 transcription factor is one of the members of the p53 family of tumor suppressors with unique biological functions in processes like neurogenesis, embryonic development and differentiation. For ... [more ▼]

The p73 transcription factor is one of the members of the p53 family of tumor suppressors with unique biological functions in processes like neurogenesis, embryonic development and differentiation. For this reason, p73 activity is tightly regulated by multiple mechanisms, including transcription and post-translational modifications. Here, we identified a novel regulatory loop between TAp73 and the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32). TRIM32, a new direct p73 transcriptional target in the context of neural progenitor cells, is differentially regulated by p73. Although TAp73 binds to the TRIM32 promoter and activates its expression, TAp73-induced TRIM32 expression is efficiently repressed by DNp73. TRIM32 in turn physically interacts with TAp73 and promotes its ubiquitination and degradation, impairing p73-dependent transcriptional activity. This mutual regulation between p73 and TRIM32 constitutes a novel feedback loop, which might have important implications in central nervous system development as well as relevance in oncogenesis, and thus emerges as a possible therapeutic target. [less ▲]

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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 detailDerivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling.
Reinhardt, Peter; Glatza, Michael; Hemmer, Kathrin et al

in PLoS ONE (2013), 8(3), 59252

Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even ... [more ▼]

Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even small variability within the cell populations for screening could easily invalidate an entire campaign. Neurodegenerative assays are particularly challenging because neurons are post-mitotic and cannot be expanded for implementation in HTS. Therefore, HTS for neuroprotective compounds requires a cell type that is robustly expandable and able to differentiate into all of the neuronal subtypes involved in disease pathogenesis. Here, we report the derivation and propagation using only small molecules of human neural progenitor cells (small molecule neural precursor cells; smNPCs). smNPCs are robust, exhibit immortal expansion, and do not require cumbersome manual culture and selection steps. We demonstrate that smNPCs have the potential to clonally and efficiently differentiate into neural tube lineages, including motor neurons (MNs) and midbrain dopaminergic neurons (mDANs) as well as neural crest lineages, including peripheral neurons and mesenchymal cells. These properties are so far only matched by pluripotent stem cells. Finally, to demonstrate the usefulness of smNPCs we show that mDANs differentiated from smNPCs with LRRK2 G2019S are more susceptible to apoptosis in the presence of oxidative stress compared to wild-type. Therefore, smNPCs are a powerful biological tool with properties that are optimal for large-scale disease modeling, phenotypic screening, and studies of early human development. [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 detailAnti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice.
Worlitzer, Maik Ma; Bunk, Eva C.; Hemmer, Kathrin et al

in Stem cell research & therapy (2012), 3(4), 33

ABSTRACT: INTRODUCTION: The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how ... [more ▼]

ABSTRACT: INTRODUCTION: The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, affects adult neurogenesis and, therefore, modulates the brain's potential for self-regeneration. METHODS: Neural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-alpha infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson's disease background. Microscopic methods and behavioral tests were used to analyze samples. RESULTS: Here, we demonstrate that differences in the chronicity of TNF-alpha application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-alpha treatment, mimicking Parkinson's disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson's disease-associated behavior, which was correlated with long-term anti-inflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced. CONCLUSIONS: We conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson's disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson's disease and thereby attenuate dysfunctions of basalganglian motor-control. [less ▲]

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See detailAbundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus.
Kelava, Iva; Reillo, Isabel; Murayama, Ayako Y. et al

in Cerebral Cortex (2012), 22(2), 469-81

Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of ... [more ▼]

Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), glutamate aspartate transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur at similar relative abundance in the marmoset SVZ as in human and ferret. The proportion of progenitors in M-phase was lower in embryonic marmoset than developing ferret neocortex, raising the possibility of a longer cell cycle. Fitting the gyrification indices of 26 anthropoid species to an evolutionary model suggested that the marmoset evolved from a gyrencephalic ancestor. Our results suggest that a high relative abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly and that the marmoset's lissencephaly evolved secondarily by changing progenitor parameters other than progenitor type. [less ▲]

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