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30 Publications visible to you, out of a total of 30
Molecular diversity of diencephalic astrocytes reveals adult astrogenesis regulated by Smad4.

Abstract (Expand)

Astrocytes regulate brain-wide functions and also show region-specific differences, but little is known about how general and region-specific functions are aligned at the single-cell level. To explore … this, we isolated adult mouse diencephalic astrocytes by ACSA-2-mediated magnetic-activated cell sorting (MACS). Single-cell RNA-seq revealed 7 gene expression clusters of astrocytes, with 4 forming a supercluster. Within the supercluster, cells differed by gene expression related to ion homeostasis or metabolism, with the former sharing gene expression with other regions and the latter being restricted to specific regions. All clusters showed expression of proliferation-related genes, and proliferation of diencephalic astrocytes was confirmed by immunostaining. Clonal analysis demonstrated low level of astrogenesis in the adult diencephalon, but not in cerebral cortex grey matter. This led to the identification of Smad4 as a key regulator of diencephalic astrocyte in vivo proliferation and in vitro neurosphere formation. Thus, astrocytes show diverse gene expression states related to distinct functions with some subsets being more widespread while others are more regionally restricted. However, all share low-level proliferation revealing the novel concept of adult astrogenesis in the diencephalon.

Authors: Stefanie Ohlig, Solène Clavreul, Manja Thorwirth, Tatiana Simon-Ebert, Riccardo Bocchi, Sabine Ulbricht, Nirmal Kannayian, Moritz Rossner, Swetlana Sirko, Pawel Smialowski, Judith Fischer-Sternjak, Magdalena Götz

Date Published: 2nd Nov 2021

Publication Type: Journal

Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2.

Abstract (Expand)

Astrocytes are a viable source for generating new neurons via direct conversion. However, little is known about the neurogenic cascades triggered in astrocytes from different regions of the CNS. Here, … we examine the transcriptome induced by the proneural factors Ascl1 and Neurog2 in spinal cord-derived astrocytes in vitro. Each factor initially elicits different neurogenic programs that later converge to a V2 interneuron-like state. Intriguingly, patch sequencing (patch-seq) shows no overall correlation between functional properties and the transcriptome of the heterogenous induced neurons, except for K-channels. For example, some neurons with fully mature electrophysiological properties still express astrocyte genes, thus calling for careful molecular and functional analysis. Comparing the transcriptomes of spinal cord- and cerebral-cortex-derived astrocytes reveals profound differences, including developmental patterning cues maintained in vitro. These relate to the distinct neuronal identity elicited by Ascl1 and Neurog2 reflecting their developmental functions in subtype specification of the respective CNS region.

Authors: J Kempf, K Knelles, B A Hersbach, D Petrik, T Riedemann, V Bednarova, A Janjic, T Simon-Ebert, W Enard, P Smialowski, M Götz, G Masserdotti

Date Published: 20th Jul 2021

Publication Type: Journal

Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity.

Abstract (Expand)

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an … experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6(+), and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.

Authors: M. Hiltensperger, E. Beltran, R. Kant, S. Tyystjarvi, G. Lepennetier, H. Dominguez Moreno, I. J. Bauer, S. Grassmann, S. Jarosch, K. Schober, V. R. Buchholz, S. Kenet, C. Gasperi, R. Ollinger, R. Rad, A. Muschaweckh, C. Sie, L. Aly, B. Knier, G. Garg, A. M. Afzali, L. A. Gerdes, T. Kumpfel, S. Franzenburg, N. Kawakami, B. Hemmer, D. H. Busch, T. Misgeld, K. Dornmair, T. Korn

Date Published: 9th Jun 2021

Publication Type: Journal

White matter aging drives microglial diversity.

Abstract (Expand)

Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white … matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer's disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.

Authors: S. Safaiyan, S. Besson-Girard, T. Kaya, L. Cantuti-Castelvetri, L. Liu, H. Ji, M. Schifferer, G. Gouna, F. Usifo, N. Kannaiyan, D. Fitzner, X. Xiang, M. J. Rossner, M. Brendel, O. Gokce, M. Simons

Date Published: 7th Apr 2021

Publication Type: Journal

MicroRNAs from extracellular vesicles as a signature for Parkinson's disease.

Abstract (Expand)

In the present study, we have demonstrated that extracellular vesicles (EVs) derived from cerebrospinal fluid (CSF) represent a promising source for the identification of a novel miRNA signatures in … Parkinson's disease (PD). Using next‐generation small‐RNA sequencing, we present for the first time the complete and quantitative microRNAome of EVs isolated from human CSF of PD and age‐correlated controls (CTR). In parallel, we performed CSF proteomic profiling of overlapping patient cohorts, which revealed the deregulation of disease‐relevant pathways similar to the ones obtained with the parallel miRNA analyses, supporting the results for the identified signature.

Authors: Lucas Caldi Gomes, Anna-Elisa Roser, Gaurav Jain, Tonatiuh Pena Centeno, Fabian Maass, Lukas Schilde, Caroline May, Anja Schneider, Mathias Bähr, Katrin Marcus, André Fischer, Paul Lingor

Date Published: 5th Apr 2021

Publication Type: Journal

Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics.

Abstract (Expand)

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, … poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca<sup>2+</sup> dynamics and promoted NSC activation. We further discovered a Ca<sup>2+</sup> signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca<sup>2+</sup> pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca<sup>2+</sup> fluxes to mimic quiescent-state-like Ca<sup>2+</sup> dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.

Authors: Archana Gengatharan, Sarah Malvaut, Alina Marymonchyk, Majid Ghareghani, Marina Snapyan, Judith Fischer-Sternjak, Jovica Ninkovic, Magdalena Götz, Armen Saghatelyan

Date Published: 4th Feb 2021

Publication Type: Journal

Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation.

Abstract (Expand)

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal … structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.

Authors: Mehrnoosh Jafari, Adrian-Minh Schumacher, Nicolas Snaidero, Emily M Ullrich Gavilanes, Tradite Neziraj, Virág Kocsis-Jutka, Daniel Engels, Tanja Jürgens, Ingrid Wagner, Juan Daniel Flórez Weidinger, Stephanie S Schmidt, Eduardo Beltrán, Nellwyn Hagan, Lisa Woodworth, Dimitry Ofengeim, Joseph Gans, Fred Wolf, Mario Kreutzfeldt, Ruben Portugues, Doron Merkler, Thomas Misgeld, Martin Kerschensteiner

Date Published: 25th Jan 2021

Publication Type: Journal

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