22 research outputs found
MicroRNAs and orphan nuclear receptor GCNF as novel regulators of human neural stem cell differentiation and neuronal subtype specification
No full textMicroRNAs (miRNAs) are currently recognized as important regulators of neural development. However, given the large number of miRNA species in existence, our understanding of miRNA-based regulation during neurogenesis remains incomplete, in particular with regard to human neural development. Human pluripotent stem cell (hPSC)-based neural stem cells (NSCs) now offer the possibility to study the function of miRNAs in association with early human neuronal differentiation. Thus, the aim of this study was to analyze the impact of miRNAs and their downstream effectors on human neuronal differentiation and subtype specification using a specific population of long-term
self-renewing neuroepithelial-like stem (lt-NES) cells. First, a miRNA profiling analysis was performed covering the progression from human embryonic stem cells to neurons with lt-NES cells as a stable intermediate. Subsequent functional analyses demonstrated that miR-153, miR-181a/a* and miR-324-5p/3p are able to promote neuronal differentiation of lt-NES cells, similar to the impact of the neuronal-associated miR-124 and miR-125b. In addition, miR-124, miR-125b and miR-181a/a* were found to modulate the neuronal subtype composition of differentiating lt-NES cells, and transfection with respective miRNA oligonucleotides induced differentiation towards a dopaminergic phenotype. Further experiments using hPSC-derived floor plate progenitor cells, a more authentic source for midbrain dopaminergic neurons, confirmed the positive function of miR-181a and the negative function of miR-124 during dopaminergic differentiation. The last part of the thesis focused on deciphering the targets and down-stream effectors of miR-181a. With regard to its role as promoter of neuronal differentiation, miR-181a down-regulates several factors involved in NSC maintenance, including the orphan nuclear receptor GCNF. GCNF is a known transcriptional repressor of pluripotency genes, however, evidence collected in this work points to a yet unrecognized role for GCNF in human NSCs. Specifically, direct targeting of GCNF by miR-181a resulted in an increased rate of neuronal differentiation. Conversely, GCNF overexpression interfered with neuronal differentiation, while preserving the characteristic neural rosette morphology of undifferentiated lt-NES cells. On a mechanistic level, GCNF might act as a suppressor of pro-neural bHLH gene expression, similar to the role of Notch signaling. Indeed, ectopic expression of GCNF partially compensated for Notch inhibition by the gamma-secretase inhibitor DAPT. In addition to this general effect on neuronal differentiation, GCNF has a specific negative effect on the dopaminergic lineage. Thus, the action of miR-181a on GCNF might also account for the miR-181a-induced dopaminergic differentiation. Overexpression of miR-181a in lt-NES cells also increased Wnt activity, which might further contribute to the generation of dopaminergic neurons. Taken together, this work describes a comprehensive analysis from miRNA profiling to the functional study of specific miRNAs in the context of human neuronal differentiation. Based on these analyses, a mechanistic interaction between miR-181a and GCNF in regulating human NSC fate was discovered. Furthermore, this study is the first to describe a miRNA – miR-181a – that promotes the generation of dopaminergic neurons. These findings could be exploited to develop novel approaches for human neural stem cell maintenance as well as the in vitro differentiation of dopaminergic neurons
Using a video presentation on variance and covariance in the teaching of statistics
No full textAusterschmidt K-L, Stappert A, Heusel H, Bebermeier S. Using a video presentation on variance and covariance in the teaching of statistics. Teaching Statistics. An International Journal for Statistics and Data Science Teaching. 2021.We outline the use and evaluation of a video presentation about variance and covariance developed to motivate students to process the topics and to enhance their skills. We outline the structure and the content of the video presentation and present data of an evaluation study. Students in different subjects who must pass statistics courses (N = 114) participated in an online survey with randomized controlled design and repeated measurement. Results indicate that students who watched the video presentation significantly improved on their skills, compared to a control group reading a textbook section about the same topics. The video presentation was judged as more satisfying and useful for learning than the text. We discuss application scenarios and further teaching implications. Ideally a longitudinal study should investigate effects of continuous learning with video presentations, changes in motivation, anxiety, and attitudes as well as effects for students of different subjects
Notch/Hes signaling and miR-9 engage in complex feedback interactions controlling neural progenitor cell proliferation and differentiation
No full textMicroRNAs Engage in Complex Circuits Regulating Adult Neurogenesis
No full textThe finding that the adult mammalian brain is still capable of producing neurons has ignited a new field of research aiming to identify the molecular mechanisms regulating adult neurogenesis. An improved understanding of these mechanisms could lead to the development of novel approaches to delay cognitive decline and facilitate neuroregeneration in the adult human brain. Accumulating evidence suggest microRNAs (miRNAs), which represent a class of post-transcriptional gene expression regulators, as crucial part of the gene regulatory networks governing adult neurogenesis. This review attempts to illustrate how miRNAs modulate key processes in the adult neurogenic niche by interacting with each other and with transcriptional regulators. We discuss the function of miRNAs in adult neurogenesis following the life-journey of an adult-born neuron from the adult neural stem cell (NSCs) compartment to its final target site. We first survey how miRNAs control the initial step of adult neurogenesis, that is the transition of quiescent to activated proliferative adult NSCs, and then go on to discuss the role of miRNAs to regulate neuronal differentiation, survival, and functional integration of the newborn neurons. In this context, we highlight miRNAs that converge on functionally related targets or act within cross talking gene regulatory networks. The cooperative manner of miRNA action and the broad target repertoire of each individual miRNA could make the miRNA system a promising tool to gain control on adult NSCs in the context of therapeutic approaches
Reciprocal Regulation between Bifunctional miR-9/9∗ and its Transcriptional Modulator Notch in Human Neural Stem Cell Self-Renewal and Differentiation
No full textSummaryTight regulation of the balance between self-renewal and differentiation of neural stem cells is crucial to assure proper neural development. In this context, Notch signaling is a well-known promoter of stemness. In contrast, the bifunctional brain-enriched microRNA miR-9/9∗ has been implicated in promoting neuronal differentiation. Therefore, we set out to explore the role of both regulators in human neural stem cells. We found that miR-9/9∗ decreases Notch activity by targeting NOTCH2 and HES1, resulting in an enhanced differentiation. Vice versa, expression levels of miR-9/9∗ depend on the activation status of Notch signaling. While Notch inhibits differentiation of neural stem cells, it also induces miR-9/9∗ via recruitment of the Notch intracellular domain (NICD)/RBPj transcriptional complex to the miR-9/9∗_2 genomic locus. Thus, our data reveal a mutual interaction between bifunctional miR-9/9∗ and the Notch signaling cascade, calibrating the delicate balance between self-renewal and differentiation of human neural stem cells
The Aurora space launcher concept
No full textThis paper gives an overview about the Aurora reusable space launcher concept study that was initiated in late-2015/early-
2016. Within the Aurora study, several spaceplane-like vehicle configurations with different geometries, propulsion systems
and mission profiles will be designed, investigated and evaluated with respect to their technical and economic feasibility.
The first part of this paper will discuss the study logic and the current status of the Aurora studies and introduces the first
vehicle configurations and their system design status. As the identification of highly efficient structural designs is of particular
interest for Aurora, the structural design and analysis approach will be discussed in higher level of detail. A special
design feature of the Aurora vehicle configurations is the utilization of the novel thin-ply composite material technology for
structural mass reductions. Therefore, the second part of this paper will briefly discuss this technology and investigate the
application and potential mass savings on vehicle level within simplified structural analysis studies. The results indicate that
significant mass savings could be possible. Finally, an outlook on the next steps is provided
Correction: MicroRNA-Based Promotion of Human Neuronal Differentiation and Subtype Specification
No full textValidation of the identified microRNA expression patterns in two different cell lines.
No full text<p>(<b>A</b>–<b>D</b>) Northern blot analyses showing expression of miRNAs in human ES cells (ES), lt-NES cells (NES) and lt-NES cells differentiated for 15 days (ND15) and 30 days (ND30) from the I3 and H9.2 cell lines. Representative miRNAs for the different expression groups identified are shown (Group 1, <b>A</b>; Group 2, <b>B</b>; Group 3, <b>C</b>). (<b>D</b>) Northern blot analyses showing expression of miR-181a and miR-181a* in the samples described above. Putative miRNA precursors are indicated by “pre”; mature miRNAs are indicated by “miR”. U6 snRNA was used as loading control. (<b>E, F</b>) qRT-PCR analyses monitoring expression of miR-153, miR-324-5p, miR-324-3p, miR-181a and miR-181a* in the samples described above from the I3 (<b>E</b>) and H9.2 (<b>F</b>) cell lines. Data are normalized to RNU5A snRNA reference levels and presented as average changes + SEM relative to expression in NES (baseline, set to 1; n = 3; *, p≤0.05; **, p≤0.005; ***, p≤0.0001). Abbreviations: ES, embryonic stem cells; lt-NES, long-term self-renewing neuroepithelial-like stem cells; qRT-PCR, quantitative real-time reverse transcription-polymerase chain reaction; snRNA, small nuclear RNA.</p
