References of "Schwamborn, Jens Christian 50003060"
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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 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 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 & 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 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 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 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 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 detailRegulatory feedback loop between TP73 and TRIM32.
Gonzalez-Cano, L.; Hillje, Anna-Lena UL; Fuertes-Alvarez, S. et al

in Cell Death & 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 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 detailRegrowing the adult brain: NF-kappaB controls functional circuit formation and tissue homeostasis in the dentate gyrus.
Imielski, Yvonne; Schwamborn, Jens Christian UL; Luningschror, Patrick et al

in PLoS ONE (2012), 7(2), 30838

Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that ... [more ▼]

Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-kappaB resulted in severe defects in the neurogenic region (dentate gyrus) of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-kappaB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-kappaB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-kappaB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-kappaB to be a therapeutic target for treating cognitive and mood disorders. [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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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 detailDiscovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay.
Hoing, Susanne; Rudhard, York; Reinhardt, Peter et al

in Cell Stem Cell (2012), 11(5), 620-32

Stem cells, through their ability to both self-renew and differentiate, can produce a virtually limitless supply of specialized cells that behave comparably to primary cells. We took advantage of this ... [more ▼]

Stem cells, through their ability to both self-renew and differentiate, can produce a virtually limitless supply of specialized cells that behave comparably to primary cells. We took advantage of this property to develop an assay for small-molecule-based neuroprotection using stem-cell-derived motor neurons and astrocytes, together with activated microglia as a stress paradigm. Here, we report on the discovery of hit compounds from a screen of more than 10,000 small molecules. These compounds act through diverse pathways, including the inhibition of nitric oxide production by microglia, activation of the Nrf2 pathway in microglia and astrocytes, and direct protection of neurons from nitric-oxide-induced degeneration. We confirm the activity of these compounds using human neurons. Because microglial cells are activated in many neurological disorders, our hit compounds could be ideal starting points for the development of new drugs to treat various neurodegenerative and neurological diseases. [less ▲]

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See detailDirect reprogramming of fibroblasts into neural stem cells by defined factors.
Han, Dong Wook; Tapia, Natalia; Hermann, Andreas et al

in Cell Stem Cell (2012), 10(4), 465-72

Recent studies have shown that defined sets of transcription factors can directly reprogram differentiated somatic cells to a different differentiated cell type without passing through a pluripotent state ... [more ▼]

Recent studies have shown that defined sets of transcription factors can directly reprogram differentiated somatic cells to a different differentiated cell type without passing through a pluripotent state, but the restricted proliferative and lineage potential of the resulting cells limits the scope of their potential applications. Here we show that a combination of transcription factors (Brn4/Pou3f4, Sox2, Klf4, c-Myc, plus E47/Tcf3) induces mouse fibroblasts to directly acquire a neural stem cell identity-which we term as induced neural stem cells (iNSCs). Direct reprogramming of fibroblasts into iNSCs is a gradual process in which the donor transcriptional program is silenced over time. iNSCs exhibit cell morphology, gene expression, epigenetic features, differentiation potential, and self-renewing capacity, as well as in vitro and in vivo functionality similar to those of wild-type NSCs. We conclude that differentiated cells can be reprogrammed directly into specific somatic stem cell types by defined sets of specific transcription factors. [less ▲]

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