TY  - JOUR
AB  - Astrocytes play key roles in brain function, but how these are orchestrated by transcription factors (TFs) in the adult brain and aligned with astrocyte heterogeneity is largely unknown. Here we examined the localization and function of the novel astrocyte TF Trps1 (Transcriptional Repressor GATA Binding 1) and the well-known astrocyte TF Sox9 by Cas9-mediated deletion using Mokola-pseudotyped lentiviral delivery into the adult cerebral cortex. Trps1 and Sox9 levels showed heterogeneity among adult cortical astrocytes, which prompted us to explore the effects of deleting either Sox9 or Trps1 alone or simultaneously at the single-cell (by patch-based single-cell transcriptomics) and tissue levels (by spatial transcriptomics). This revealed TF-specific functions in astrocytes, such as synapse maintenance with the strongest effects on synapse number achieved by Trps1 deletion and a common effect on immune response. In addition, spatial transcriptomics showed non-cell-autonomous effects on the surrounding cells, such as oligodendrocytes and other immune cells with TF-specific differences on the type of immune cells: Trps1 deletion affecting monocytes specifically, while Sox9 deletion acting mostly on microglia and deletion of both TF affecting mostly B cells. Taken together, this study reveals novel roles of Trps1 and Sox9 in adult astrocytes and their communication with other glial and immune cells.
AU  - Natarajan, P.
AU  - Koupourtidou, C.
AU  - de Resseguier, T.*
AU  - Thorwirth, M.
AU  - Bocchi, R.
AU  - Fischer-Sternjak, J.
AU  - Gleiss, S.*
AU  - Rodrigues, D.*
AU  - Myoga, M.H.*
AU  - Ninkovic, J.
AU  - Masserdotti, G.
AU  - Götz, M.
C1  - 72574
C2  - 56657
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 22
TI  - Single cell deletion of the transcription factors Trps1 and Sox9 in astrocytes reveals novel functions in the adult cerebral cortex.
JO  - Glia
PB  - Wiley
PY  - 2024
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The human macula is a highly specialized retinal region with pit-like morphology and rich in cones. How Müller cells, the principal glial cell type in the retina, are adapted to this environment is still poorly understood. We compared proteomic data from cone- and rod-rich retinae from human and mice and identified different expression profiles of cone- and rod-associated Müller cells that converged on pathways representing extracellular matrix and cell adhesion. In particular, epiplakin (EPPK1), which is thought to play a role in intermediate filament organization, was highly expressed in macular Müller cells. Furthermore, EPPK1 knockout in a human Müller cell-derived cell line led to a decrease in traction forces as well as to changes in cell size, shape, and filopodia characteristics. We here identified EPPK1 as a central molecular player in the region-specific architecture of the human retina, which likely enables specific functions under the immense mechanical loads in vivo.
AU  - Kaplan, L.*
AU  - Drexler, C.G.*
AU  - Pfaller, A.M.*
AU  - Brenna, S.*
AU  - Wunderlich, K.A.*
AU  - Dimitracopoulos, A.*
AU  - Merl-Pham, J.
AU  - Perez, M.T.*
AU  - Schlötzer-Schrehardt, U.*
AU  - Enzmann, V.*
AU  - Samardzija, M.*
AU  - Puig, B.*
AU  - Fuchs, P.*
AU  - Franze, K.*
AU  - Hauck, S.M.
AU  - Grosche, A.*
C1  - 66605
C2  - 53239
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 391-414
TI  - Retinal regions shape human and murine Müller cell proteome profile and functionality.
JO  - Glia
VL  - 71
IS  - 2
PB  - Wiley
PY  - 2023
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecular responses following exposure to a high-fat high-sugar (HFHS) diet, specifically in the ARC. Using RNA sequencing and proteomics, we showed that astrocytes have a distinct transcriptomic and proteomic profile dependent on their anatomical location, with a major proteomic reprogramming in hypothalamic astrocytes. By ARC single-cell sequencing, we observed that a HFHS diet dictates time- and cell- specific transcriptomic responses, revealing that astrocytes have the most distinct regulatory pattern compared to other cell types. Lastly, we topographically and molecularly characterized astrocytes expressing glial fibrillary acidic protein and/or aldehyde dehydrogenase 1 family member L1 in the ARC, of which the abundance was significantly increased, as well as the alteration in their spatial and molecular profiles, with a HFHS diet. Together, our results provide a detailed multi-omics view on the spatial and temporal changes of astrocytes particularly in the ARC during different time points of adaptation to a high calorie diet.
AU  - Lutomska, L.M.
AU  - Miok, V.
AU  - Krahmer, N.
AU  - Gonzales García, I.
AU  - Gruber, T.
AU  - Le Thuc, O.
AU  - Murat, C.*
AU  - Legutko, B.
AU  - Sterr, M.
AU  - Saher, G.*
AU  - Lickert, H.
AU  - Müller, T.D.
AU  - Ussar, S.
AU  - Tschöp, M.H.
AU  - Lutter, D.
AU  - García-Cáceres, C.
C1  - 65652
C2  - 52852
SP  - 2062-2078
TI  - Diet triggers specific responses of hypothalamic astrocytes in time and region dependent manner.
JO  - Glia
VL  - 70
IS  - 11
PY  - 2022
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Unlike microglia and NG2 glia, astrocytes are incapable of migrating to sites of injury in the posttraumatic cerebral cortex, instead relying on proliferation to replenish their numbers and distribution in the affected region. However, neither the spectrum of their proliferative repertoire nor their postinjury distribution has been examined in vivo. Using a combination of different thymidine analogs and clonal analysis in a model of repetitive traumatic brain injury, we show for the first time that astrocytes that are quiescent following an initial injury can be coerced to proliferate after a repeated insult in the cerebral cortex grey matter. Interestingly, this process is promoted by invasion of monocytes to the injury site, as their genetic ablation (using CCR2(-/-)mice) increased the number of repetitively dividing astrocytes at the expense of newly proliferating astrocytes in repeatedly injured parenchyma. These differences profoundly affected both the distribution of astrocytes and recovery period for posttraumatic behavior deficits suggesting key roles of astrocyte self-renewal in brain repair after injury.
AU  - Lange Canhos, L.
AU  - Chen, M.*
AU  - Falk, S.
AU  - Popper, B.*
AU  - Straub, T.*
AU  - Götz, M.
AU  - Sirko, S.
C1  - 59833
C2  - 48987
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 165-181
TI  - Repetitive injury and absence of monocytes promote astrocyte self-renewal and neurological recovery.
JO  - Glia
VL  - 69
IS  - 1
PB  - Wiley
PY  - 2021
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The Alzheimer disease-associated multifunctional low-density lipoprotein receptor-related protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knock-out (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The low-density lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic low-density lipoprotein receptor-related protein-1 for glutamatergic signaling in the context of neuron-glia interactions and stage this receptor as a contributing factor for epilepsy.
AU  - Bres, E.E.*
AU  - Safina, D.*
AU  - Müller, J.*
AU  - Bedner, P.*
AU  - Yang, H.*
AU  - Helluy, X.*
AU  - Shchyglo, O.*
AU  - Jansen, S.*
AU  - Mark, M.D.*
AU  - Esser, A.*
AU  - Steinhäuser, C.*
AU  - Herlitze, S.*
AU  - Pietrzik, C.U.*
AU  - Sirko, S.
AU  - Manahan-Vaughan, D.*
AU  - Faissner, A.*
C1  - 59477
C2  - 48840
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 2517-2549
TI  - Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.
JO  - Glia
VL  - 68
IS  - 12
PB  - Wiley
PY  - 2020
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Astrocyte heterogeneity is increasingly recognized, but still little is known about juxtavascular astrocytes with their somata directly adjacent to blood vessels, despite their importance after brain injury. As juxtavascular astrocytes originate from common progenitor cells, that is, have a clonal origin, they may intrinsically differ from other, non-juxtavascular astrocytes. To explore this, we examined the electrophysiological properties of these groups of astrocytes and the underlying ion channels. Using brain slices of BAC Aldh1l1-eGFP transgenic mice with astrocytes labeled by GFP expression, we compared juxtavascular and non-juxtavascular astrocytes in the somatosensory cortex by means of whole-cell patch-clamp recordings and immunohistochemical staining. Prior to injury, juxta- and non-juxtavascular astrocytes exhibit comparable electrophysiological properties with characteristic mostly passive conductance and a typical negative resting membrane potential. Immunohistochemical analysis of K(+)channels showed that all astrocytes were K(ir)4.1(+), but revealed an intriguing difference for K(v)4.3. The expression of K(v)4.3 in sibling astrocytes (non-juxtavascular, juxtavascular and pial) was dependent on their ontogenetic origin with lowest levels in juxtavascular astrocytes located in upper cortical layers. After traumatic brain injury (TBI), we found profound changes in the electrophysiological type of astrocytes with a predominance of non-passive properties and this pattern was significantly enriched in juxtavascular astrocytes. This was accompanied by pronounced down-regulation of K(ir)4.1 in proliferating astrocytes, which was significantly more in juxtavascular compared to non-juxtavascular astrocytes. Taken together, TBI induces profound differences in electrophysiological properties between juxtavascular and non-juxtavascular astrocytes that might be related to the preponderance of juxtavascular astrocyte proliferation.
AU  - Götz, S.*
AU  - Bribian, A.*
AU  - López-Mascaraque, L.*
AU  - Götz, M.
AU  - Grothe, B.*
AU  - Kunz, L.*
C1  - 59920
C2  - 49119
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 346-361
TI  - Heterogeneity of astrocytes: Electrophysiological properties of juxtavascular astrocytes before and after brain injury.
JO  - Glia
VL  - 69
IS  - 2
PB  - Wiley
PY  - 2020
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on myeloid-derived cell types. The extracellular immunoglobulin-like domain of TREM2 binds anionic ligands including Apolipoprotein E and Amyloid-β. The transmembrane domain interacts with its adaptor protein DAP12/TYROBP that is responsible for propagation of downstream signaling upon ligand interaction. Several sequence variants of TREM2 have been linked to different neurodegenerative diseases including Alzheimer's disease. Here, we generated HEK 293 Flp-In cell lines stably expressing human TREM2 and DAP12 using a bicistronic construct with a T2A linker sequence allowing initial expression of both proteins in stoichiometric amounts. Cell biological and biochemical analyses revealed transport of TREM2 to the cell surface, and canonical sequential proteolytic processing and shedding of TREM2 (sTREM2). The functionality of this cell system was demonstrated by detection of phosphorylated spleen tyrosine kinase (SYK) upon stimulation of TREM2 with the anionic membrane lipid phosphatidylserine or anti-TREM2 antibodies. Using this cell model, we demonstrated impaired signaling of disease associated TREM2 variants. We also identified a monoclonal antibody against the stalk region of TREM2 with agonistic activity. Activation of TREM2-DAP12 signaling with the monoclonal antibody and the partial loss of function of disease associated variants were recapitulated in induced pluripotent stem cell derived microglia. Thus, this reporter cell model represents a suitable experimental system to investigate signaling of TREM2 variants, and for the identification of ligands and compounds that modulate TREM2-DAP12 signaling. MAIN POINTS: Disease associated variants impair the signaling activity of TREM2 by distinct mechanisms. Targeting the stalk region of TREM2 with bivalent antibodies activates TREM2 signaling.
AU  - Ibach, M.*
AU  - Mathews, M.*
AU  - Linnartz-Gerlach, B.*
AU  - Theil, S.*
AU  - Kumar, S.*
AU  - Feederle, R.
AU  - Brüstle, O.*
AU  - Neumann, H.*
AU  - Walter, J.*
C1  - 60757
C2  - 49541
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease-associated variants on receptor signaling and activation by antibodies against the stalk region.
JO  - Glia
PB  - Wiley
PY  - 2020
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Bres, E.E.*
AU  - Safina, D.*
AU  - Mueller, J.*
AU  - Esser, A.*
AU  - Yang, H.*
AU  - Bedner, P.*
AU  - Helluy, X.*
AU  - Jansen, S.*
AU  - Manahan-Vaughan, D.*
AU  - Steinhaeuser, C.*
AU  - Pietrzik, C.U.*
AU  - Götz, M.
AU  - Faissner, A.*
C1  - 57789
C2  - 47900
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - E758-E758
TI  - Lrp1 loss in radial glia and their progeny - astrocytic dysfunctions contribute to spontaneous epileptogenesis.
JO  - Glia
VL  - 67
PB  - Wiley
PY  - 2019
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Chen, M.*
AU  - Sommerfeld, O.*
AU  - Popper, B.*
AU  - Sirko, S.
C1  - 57786
C2  - 47897
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - E693-E694
TI  - Proliferative activity of reactive astrocytes has a significant impact on post-traumatic behavior.
JO  - Glia
VL  - 67
PB  - Wiley
PY  - 2019
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Koupourtidou, C.
AU  - Schwarz, V.
AU  - Sanchez-Gonzalez, R.
AU  - Breunig, C.
AU  - Fischer, J.
AU  - Sirko, S.
AU  - Götz, M.
AU  - Hauck, S.M.
AU  - Stricker, S.H.
AU  - Ninkovic, J.
C1  - 57787
C2  - 47898
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - E689-E690
TI  - Tlr2 and Cxcr3 pathways modulate scar formation after traumatic brain injury.
JO  - Glia
VL  - 67
PB  - Wiley
PY  - 2019
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Pauly, D.*
AU  - Agarwal, D.*
AU  - Dana, N.*
AU  - Schäfer, N.*
AU  - Grassmann, F.*
AU  - Zhang, N.R.*
AU  - Gautam, A.K.*
AU  - Weber, B.H.F.*
AU  - Hauck, S.M.
AU  - Kim, M.*
AU  - Curcio, C.A.*
AU  - Stambolian, D.*
AU  - Li, M.*
AU  - Grosche, A.*
C1  - 57790
C2  - 47913
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - E629-E629
TI  - Glial cells shape the complement homeostasis the healthy and diseased murine retina.
JO  - Glia
VL  - 67
PB  - Wiley
PY  - 2019
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Sirko, S.
AU  - Schichor, C.*
AU  - Tonn, J.-.*
AU  - Götz, M.
C1  - 57788
C2  - 47899
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - E693-E693
TI  - Injury-induced plasticity of parenchymal astrocytes in the human cerebral cortex.
JO  - Glia
VL  - 67
PB  - Wiley
PY  - 2019
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs.
AU  - Kunze, C.
AU  - Börner, K.*
AU  - Kienle, E.*
AU  - Orschmann, T.
AU  - Rusha, E.
AU  - Schneider, M.
AU  - Radivojkov-Blagojevic, M.
AU  - Drukker, M.
AU  - Desbordes, S.C.
AU  - Grimm, D.*
AU  - Brack-Werner, R.
C1  - 52310
C2  - 43895
CY  - Hoboken
SP  - 413-427
TI  - Synthetic AAV/CRISPR vectors for blocking HIV-1 expression in persistently infected astrocytes.
JO  - Glia
VL  - 66
IS  - 2
PB  - Wiley
PY  - 2018
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Traumatic brain injury frequently affects the cerebral cortex, yet little is known about the differential effects that occur if only the gray matter (GM) is damaged or if the injury also involves the white matter (WM). To tackle this important question and directly compare similarities and differences in reactive gliosis, we performed stab wound injury affecting GM and WM (GM+) and one restricted to the GM (GM-) in the adult murine cerebral cortex. First, we examined glial reactivity in the regions affected (WM and GM) and determined the influence of WM injury on reactive gliosis in the GM comparing the same area in the two injury paradigms. In the GM+ injury microglia proliferation is increased in the WM compared with GM, while proliferating astrocytes are more abundant in the GM than in the WM. Interestingly, WM lesion exerted a strong influence on the proliferation of the GM glial cells that was most pronounced at early stages, 3 days post lesion. While astrocyte proliferation was increased, NG2 glia proliferation was decreased in the GM+ compared with GM- lesion condition. Importantly, these differences were not observed when a lesion of the same size affected only the GM. Unbiased proteomic analyses further corroborate our findings in support of a profound difference in GM reactivity when WM is also injured and revealed MIF as a key regulator of NG2 glia proliferation.
AU  - Mattugini, N.
AU  - Merl-Pham, J.
AU  - Petrozziello, E.*
AU  - Schindler, L.*
AU  - Bernhagen, J.*
AU  - Hauck, S.M.
AU  - Götz, M.
C1  - 53302
C2  - 44571
SP  - 1644-1662
TI  - Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex.
JO  - Glia
VL  - 66
IS  - 8
PY  - 2018
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Caceres, C.G.
AU  - Le Thuc, O.
AU  - Legutko, B.
AU  - Gruber, T.
AU  - Jastroch, M.
AU  - Varela, L.*
AU  - Diano, S.*
AU  - Horvath, T.*
AU  - Tschöp, M.H.
C1  - 51431
C2  - 43125
CY  - Hoboken
SP  - E217-E218
TI  - Astrocytic UCP2 is required for hypothalamic response to metabolic challenges.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - CONF
AU  - Dirscherl, P.
AU  - Jastroch, M.
AU  - Vogt-Weisenhorn, D.
AU  - Wurst, W.
C1  - 51433
C2  - 43130
CY  - Hoboken
SP  - E159-E160
TI  - Mitochondrial function in Pink1 deficient astrocytes.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Gruber, T.
AU  - Garcia-Caceres, C.
AU  - Le Thuc, O.
AU  - Legutko, B.
AU  - Horvath, T.L.*
AU  - Tschöp, M.H.
C1  - 51426
C2  - 43135
CY  - Hoboken
SP  - E511-E511
TI  - Hypercaloric environment triggers chronic remodeling of the hypothalamic vasculature via astroglial HIF1 alpha and VEGF signaling.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Heimann, G.*
AU  - Lange Canhos, L.
AU  - Frik, J.*
AU  - Jaeger, G.*
AU  - Götz, M.
AU  - Sirko, S.
C1  - 51425
C2  - 43136
CY  - Hoboken
SP  - E520-E520
TI  - Intrinsic changes in the proliferative program limit astrocyte homeostasis in the aged post-traumatic murine cerebral cortex.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Astrocytes are the most abundant cell type of the central nervous system and cover a broad range of functionalities. We report here the generation of a novel monoclonal antibody, anti-astrocyte cell surface antigen-2 (Anti-ACSA-2). Flow cytometry, immunohistochemistry and immunocytochemistry revealed that Anti-ACSA-2 reacted specifically with a not yet identified glycosylated surface molecule of murine astrocytes at all developmental stages. It did not show any labeling of non-astroglial cells such as neurons, oligodendrocytes, NG2+ cells, microglia, endothelial cells, leukocytes, or erythrocytes. Co-labeling studies of GLAST and ACSA-2 showed largely overlapping expression. However, there were also notable differences in protein expression levels and frequencies of single-positive subpopulations of cells in some regions of the CNS such as cerebellum, most prominently at early postnatal stages. In the neurogenic niches, the dentate gyrus of the hippocampus and the subventricular zone (SVZ), again a general overlap with slight differences in expression levels were observed. ACSA-2 was unlike GLAST not sensitive to papain-based tissue dissociation and allowed for a highly effective, acute, specific, and prospective purification of viable astrocytes based on a new rapid sorting procedure using Anti-ACSA-2 directly coupled to superparamagnetic MicroBeads. In conclusion, ACSA-2 appears to be a new surface marker for astrocytes, radial glia, neural stem cells and bipotent glial progenitor cells which opens up the possibility of further dissecting the characteristics of astroglial subpopulations and lineages.
AU  - Kantzer, C.G.*
AU  - Boutin, C.*
AU  - Herzig, I.D.*
AU  - Wittwer, C.*
AU  - Reiß, S.*
AU  - Tiveron, M.C.*
AU  - Drewes, J.E.*
AU  - Rockel, T.D.*
AU  - Ohlig, S.
AU  - Ninkovic, J.
AU  - Cremer, H.*
AU  - Pennartz, S.*
AU  - Jungblut, M.*
AU  - Bosio, A.*
C1  - 50943
C2  - 42976
CY  - Hoboken
SP  - 990-1004
TI  - Anti-ACSA-2 defines a novel monoclonal antibody for prospective isolation of living neonatal and adult astrocytes.
JO  - Glia
VL  - 65
IS  - 6
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Lange Canhos, L.
AU  - Falk, S.
AU  - Sirko, S.
AU  - Götz, M.
C1  - 51434
C2  - 43131
CY  - Hoboken
SP  - E121-E121
TI  - Self-renewal and differentiation potential of reactive astrocytes in vivo.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Le Thuc, O.
AU  - Legutko, B.
AU  - Gruber, T.
AU  - Li, D.*
AU  - Luquet, S.*
AU  - Tschöp, M.H.
AU  - Garcia-Caceres, C.
C1  - 51430
C2  - 43124
CY  - Hoboken
SP  - E218-E218
TI  - Hypothalamic astrocyte activity state determines systemic glucose metabolism in mice.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Legutko, B.
AU  - Gruber, T.
AU  - Caceres, C.G.
AU  - Le Thuc, O.
AU  - Horvath, T.*
AU  - Tschöp, M.H.
C1  - 51429
C2  - 43123
CY  - Hoboken
SP  - E219-E219
TI  - Astrocytic leptin and insulin signals interact to maintain systemic metabolic homeostasis.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Li, M.*
AU  - Hollunder, F.*
AU  - Loy, K.*
AU  - Bareyre, F.*
AU  - Sirko, S.
C1  - 51424
C2  - 43137
CY  - Hoboken
SP  - E543-E543
TI  - Region-specific reaction of glial cells in the brain parenchyma of adult mice following spinal cord injury.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Mattugini, N.
AU  - Ohlig, S.
AU  - Merl-Pham, J.
AU  - Kannaiyan, N.*
AU  - Hauck, S.M.
AU  - Rossner, M.J.*
AU  - Götz, M.
C1  - 51427
C2  - 43121
CY  - Hoboken
SP  - E404-E405
TI  - Differences of grey and white matter astrocytes in the intact and injured cerebral cortex.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Ohlig, S.
AU  - Irmler, M.
AU  - Lange Canhos, L.
AU  - von Bernhardi, J.T.E.*
AU  - Dimou, L.
AU  - Sirko, S.
AU  - Beckers, J.
AU  - Götz, M.
C1  - 51428
C2  - 43122
CY  - Hoboken
SP  - E401-E401
TI  - Proliferation and neural stem cell potential of diencephalic astrocytes revealed by genome-wide expression analysis is Smad4-dependent.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Pfaller, A.*
AU  - Grassmann, F.*
AU  - Hauser, A.*
AU  - Pannicke, T.*
AU  - Hauck, S.M.
AU  - Kloeting, N.*
AU  - Weber, B.*
AU  - Grosche, A.*
C1  - 51432
C2  - 43129
CY  - Hoboken
SP  - E193-E193
TI  - miRNA profile and expression analysis of Muller cells from the diabetic retina implicates a possible role of PDGF-mediated signaling in retinal glia for disease progression.
JO  - Glia
VL  - 65
PB  - Wiley
PY  - 2017
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity. GLIA 2016.
AU  - Hernandez-Garzón, E.*
AU  - Fernandez, A.M.*
AU  - Perez-Alvarez, A.*
AU  - Genis, L.*
AU  - Bascuñana, P.*
AU  - de la Rosa, R.F.*
AU  - Delgado, M.*
AU  - Pozo, M.A.*
AU  - Moreno, E.*
AU  - McCormick, P.J.*
AU  - Santi, A.*
AU  - Trueba-Saiz, A.*
AU  - García-Cáceres, C.
AU  - Tschöp, M.H.
AU  - Araque, A.*
AU  - Martin, E.D.*
AU  - Torres Aleman, I.*
C1  - 49375
C2  - 41787
SP  - 1962-1971
TI  - The insulin-like growth factor I receptor regulates glucose transport by astrocytes.
JO  - Glia
VL  - 64
IS  - 11
PY  - 2016
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - NG2-glia in the adult brain are known to proliferate and differentiate into mature and myelinating oligodendrocytes throughout lifetime. However, the role of these newly generated oligodendrocytes in the adult brain still remains little understood. Here we took advantage of the Sox10-iCreER(T2) x CAG-eGFP x Esco2(fl/fl) mouse line in which we can specifically ablate prolif-erating NG2-glia in adult animals. Surprisingly, we observed that the generation of new oligodendrocytes in the adult brain was severely affected, although the number of NG2-glia remained stable due to the enhanced proliferation of nonrecombined cells. This lack of oligodendrogenesis led to the elongation of the nodes of Ranvier as well as the associated paranodes, which could be locally rescued by myelinating oligodendrocytes differentiated from transplanted NG2-glia deriving from wildtype mice. Repetitive measurements of conduction velocity in the corpus callosum of awake animals revealed a progressive deceleration specifically in the mice lacking adult oligodendrogenesis that resulted in progressive motor deficits. In summary, here we demonstrated for the first time that axon function is not only controlled by the reliable organization of myelin, but also requires a dynamic and continuous generation of new oligodendrocytes in the adult brain.
AU  - Schneider, S.
AU  - Gruart, A.*
AU  - Grade, S.
AU  - Zhang, Y.*
AU  - Kroeger, S.*
AU  - Kirchhoff, F.*
AU  - Eichele, G.*
AU  - Delgado Garcia, J.M.*
AU  - Dimou, L.
C1  - 50066
C2  - 42184
CY  - Hoboken
SP  - 2201-2218
TI  - Decrease in newly generated oligodendrocytes leads to motor dysfunctions and changed myelin structures that can be rescued by transplanted cells.
JO  - Glia
VL  - 64
IS  - 12
PB  - Wiley-blackwell
PY  - 2016
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Beckervordersandforth, R.*
AU  - Ebert, B.
AU  - Steib, K.
AU  - Schaeffner, I.*
AU  - Keiner, S.*
AU  - Redecker, C.*
AU  - Schuster, S.C.*
AU  - Eulenburg, V.*
AU  - Toni, N.*
AU  - Moss, J.*
AU  - von Wittgenstein, J.*
AU  - Larsson, N.G.*
AU  - Götz, M.
AU  - Schlachetzki, J.*
AU  - Jagasia, R.*
AU  - Lie, D.C.
C1  - 46352
C2  - 37628
CY  - Hoboken
SP  - E297-E298
TI  - Mitochondrial dysfunction mimics the impact of ageing on hippocampal neurogenesis.
JO  - Glia
VL  - 63
PB  - Wiley-blackwell
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - In the central nervous system, NG2-glia represent a neural cell population that is distinct from neurons, astrocytes, and oligodendrocytes. While in the past the main role ascribed to these cells was that of progenitors for oligodendrocytes, in the last years it has become more obvious that they have further functions in the brain. Here, we will discuss some of the most current and highly debated issues regarding NG2-glia: Do these cells represent a heterogeneous population? Can they give rise to different progenies, and does this change under pathological conditions? How do they respond to injury or pathology? What is the role of neurotransmitter signaling between neurons and NG2-glia? We will first give an overview on the developmental origin of NG2-glia, and then discuss whether their distinct properties in different brain regions are the result of environmental influences, or due to intrinsic differences. We will then review and discuss their in vitro differentiation potential and in vivo lineage under physiological and pathological conditions, together with their electrophysiological properties in distinct brain regions and at different developmental stages. Finally, we will focus on their potential to be used as therapeutic targets in demyelinating and neurodegenerative diseases. Therefore, this review article will highlight the importance of NG2-glia not only in the healthy, but also in the diseased brain.
AU  - Dimou, L.
AU  - Gallo, V.*
C1  - 45111
C2  - 37216
CY  - Hoboken
SP  - 1429-1451
TI  - NG2-glia and their functions in the central nervous system.
JO  - Glia
VL  - 63
IS  - 8
PB  - Wiley-blackwell
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Gallo, V.*
AU  - Götz, M.
C1  - 45297
C2  - 37270
SP  - 1288-1290
TI  - Glial stem and progenitor cells shape the brain-in ontogeny, phylogeny, and disease.
JO  - Glia
VL  - 63
IS  - 8
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Gascón, S.
AU  - Murenu, E.*
AU  - Irmler, M.
AU  - Götz, M.
C1  - 46355
C2  - 37625
CY  - Hoboken
SP  - E64
TI  - Identification and successful negotiation of a metabolic checkpoint in direct neuronal reprogramming.
JO  - Glia
VL  - 63
PB  - Wiley-blackwell
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Here, we review the stem cell hallmarks of endogenous neural stem cells (NSCs) during development and in some niches of the adult mammalian brain to then compare these with reactive astrocytes acquiring stem cell hallmarks after traumatic and ischemic brain injury. Notably, even endogenous NSCs including the earliest NSCs, the neuroepithelial cells, generate in most cases only a single type of progeny and self-renew only for a rather short time in vivo. In vitro, however, especially cells cultured under neurosphere conditions reveal a larger potential and long-term self-renewal under the influence of growth factors. This is rather well comparable to reactive astrocytes in the traumatic or ischemic brain some of which acquire neurosphere-forming capacity including multipotency and long-term self-renewal in vitro, while they remain within their astrocyte lineage in vivo. Both reactive astrocytes and endogenous NSCs exhibit stem cell hallmarks largely in vitro, but their lineage differs in vivo. Both populations generate largely a single cell type in vivo, but endogenous NSCs generate neurons and reactive astrocytes remain in the astrocyte lineage. However, at some early postnatal stages or in some brain regions reactive astrocytes can be released from this fate restriction, demonstrating that they can also enact neurogenesis. Thus, reactive astrocytes and NSCs share many characteristic hallmarks, but also exhibit key differences. This conclusion is further substantiated by genome-wide expression analysis comparing NSCs at different stages with astrocytes from the intact and injured brain parenchyma.
AU  - Götz, M.
AU  - Sirko, S.
AU  - Beckers, J.
AU  - Irmler, M.
C1  - 44841
C2  - 37055
CY  - Hoboken
SP  - 1452-1468
TI  - Reactive astrocytes as neural stem or progenitor cells: In vivo lineage, In vitro potential, and genome-wide expression analysis.
JO  - Glia
VL  - 63
IS  - 8
PB  - Wiley-blackwell
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Malik, V.*
AU  - Klaus, J.
AU  - Rajarathinam, S.*
AU  - Neumann, I.*
AU  - Rupprecht, R.*
AU  - di Benedetto, B.*
C1  - 46353
C2  - 37627
CY  - Hoboken
SP  - E407
TI  - Antidepressants increase expression of the trophic factor GDF15 in astrocytes and enhance their plasticity at the glia-vasculature interface.
JO  - Glia
VL  - 63
PB  - Wiley-blackwell
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Schneider, S.
AU  - Simon, C.*
AU  - Eichele, G.*
AU  - Götz, M.
AU  - Dimou, L.
C1  - 46354
C2  - 37626
CY  - Hoboken
SP  - E105-E106
TI  - Genetic ablation of proliferating NG2-glia in the adult brain.
JO  - Glia
VL  - 63
PB  - Wiley-blackwell
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Sirko, S.
C1  - 46351
C2  - 37629
CY  - Hoboken
SP  - E70-E71
TI  - Age-related alterations of proliferative capacity and the stem cell potential in reactive astrocytes.
JO  - Glia
VL  - 63
PB  - Wiley-blackwell
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins-Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere-forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes.
AU  - Sirko, S.
AU  - Irmler, M.
AU  - Gascón, S.
AU  - Bek, S.
AU  - Schneider, S.
AU  - Dimou, L.
AU  - Obermann, J.
AU  - de Souza Paiva, D.*
AU  - Poirier, F.*
AU  - Beckers, J.
AU  - Hauck, S.M.
AU  - Barde, Y.A.*
AU  - Götz, M.
C1  - 46542
C2  - 37639
SP  - 2340-2361
TI  - Astrocyte reactivity after brain injury -  the role of galectins 1 and 3.
JO  - Glia
VL  - 63
IS  - 12
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - In the adult brain NG2-glia continuously generate mature, myelinating oligodendrocytes. To which extent the differentiation process is common to all NG2-glia and whether distinct pools are recruited for repair under physiological and pathological conditions still needs clarification. Here, we aimed at investigating the differentiation potential of adult NG2-glia that specifically express the G-protein coupled receptor 17 (GPR17), a membrane receptor that regulates the differentiation of these cells at postnatal stages. To this aim, we generated the first BAC transgenic GPR17-iCreERT2 mouse line for fate mapping studies. In these mice, under physiological conditions, GPR17+ cells -in contrast to GPR17- NG2-glia- did not differentiate within 3 months, a peculiarity that was overcome after cerebral damage induced by acute injury or ischemia. After these insults, GPR17+ NG2-glia rapidly reacted to the damage and underwent maturation, suggesting that they represent a 'reserve pool' of adult progenitors maintained for repair purposes.
AU  - Viganò, F.
AU  - Schneider, S.*
AU  - Cimino, M.*
AU  - Bonfanti, E.*
AU  - Gelosa, P.*
AU  - Sironi, L.*
AU  - Abbracchio, M.P.*
AU  - Dimou, L.
C1  - 47645
C2  - 39436
SP  - 287-299
TI  - GPR17 expressing NG2-Glia: Oligodendrocyte progenitors serving as a reserve pool after injury.
JO  - Glia
VL  - 64
IS  - 2
PY  - 2015
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild-type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1-ir), cluster of differentiation 68 (CD68-ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1-ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1-ir comparable with WT mice but had significantly lower CD68-ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1-ir, and db/db mice showed increase of CD68-ir. Obese MC4R KO mice fed a SC diet had comparable iba1-ir and CD68-ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon-like peptide-1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity.
AU  - Gao, Y.
AU  - Ottaway, N.*
AU  - Schriever, S.C.
AU  - Legutko, B.
AU  - García-Cáceres, C.
AU  - de la Fuente, E.
AU  - Mergen, C.
AU  - Bour, S.
AU  - Thaler, J.P.*
AU  - Seeley, R.J.*
AU  - Filosa, J.*
AU  - Stern, J.E.*
AU  - Perez-Tilve, D.*
AU  - Schwartz, M.W.*
AU  - Tschöp, M.H.
AU  - Yi, C.-X.
C1  - 28692
C2  - 33525
SP  - 17-25
TI  - Hormones and diet, but not body weight, control hypothalamic microglial activity.
JO  - Glia
VL  - 62
IS  - 1
PB  - Wiley-Blackwell
PY  - 2014
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Myelin loss is frequently observed in human Alzheimer's disease (AD) and may constitute to AD-related cognitive decline. A potential source to repair myelin defects are the oligodendrocyte progenitor cells (OPCs) present in an adult brain. However, until now, little is known about the reaction of these cells toward amyloid plaque deposition neither in human AD patients nor in the appropriate mouse models. Therefore, we analyzed cells of the oligodendrocyte lineage in a mouse model with chronic plaque deposition (APPPS1 mice) and samples from human patients. In APPPS1 mice defects in myelin integrity and myelin amount were prevalent at 6 months of age but normalized to control levels in 9-month-old mice. Concomitantly, we observed an increase in the proliferation and differentiation of OPCs in the APPPS1 mice at this specific time window (6-8 months) implying that improvements in myelin aberrations may result from repair mechanisms mediated by OPCs. However, while we observed a higher number of cells of the oligodendrocyte lineage (Olig2+ cells) in APPPS1 mice, OLIG2+ cells were decreased in number in postmortem human AD cortex. Our data demonstrate that oligodendrocyte progenitors specifically react to amyloid plaque deposition in an AD-related mouse model as well as in human AD pathology, although with distinct outcomes. Strikingly, possible repair mechanisms from newly generated oligodendrocytes are evident in APPPS1 mice, whereas a similar reaction of oligodendrocyte progenitors seems to be strongly limited in final stages of human AD pathology.
AU  - Behrendt, G.*
AU  - Baer, K.*
AU  - Buffo, A.*
AU  - Curtis, M.A.*
AU  - Faull, R.L.*
AU  - Rees, M.I.*
AU  - Götz, M.
AU  - Dimou, L.
C1  - 11242
C2  - 30572
SP  - 273-286
TI  - Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men.
JO  - Glia
VL  - 61
IS  - 2
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Reactive glia, including astroglia and oligodendrocyte progenitors (OPCs) are at the core of the reaction to injury in the mammalian brain with initially beneficial and later partially adverse functions such as scar formation. Given the different glial composition in the adult zebrafish brain with radial ependymoglia but no parenchymal astrocytes, we examined the glial response to an invasive stab wound injury model in the adult zebrafish telencephalon. Strikingly, already a few days after injury the wound was closed without any scar tissue. Similar to mammals, microglia cells reacted first and accumulated close to the injury site, while neither GFAP+ radial ependymoglia nor adult OPCs were recruited to the injury site. Moreover, OPCs failed to increase their proliferation after this injury, while the number of proliferating GFAP+ glia was increased until 7 days after injury. Importantly, neurogenesis was also increased after injury, generating additional neurons recruited to the parenchyma which survived for several months. Thus, these data suggest that the specific glial environment in the adult zebrafish telencephalon is not only permissive for long-term neuronal survival, but avoids scar formation. Invasive injury in the adult zebrafish telencephalon may therefore provide a useful model to untangle the molecular mechanisms involved in these beneficial glial reactions.
AU  - Baumgart, E.V.
AU  - Barbosa, J.S.
AU  - Bally-Cuif, L.*
AU  - Götz, M.
AU  - Ninkovic, J.
C1  - 6807
C2  - 29291
SP  - 343-357
TI  - Stab wound injury of the zebrafish telencephalon: A model for comparative analysis of reactive gliosis.
JO  - Glia
VL  - 60
IS  - 3
PB  - Wiley-Blackwell
PY  - 2012
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The zebrafish has become an important model organism to study myelination during development and after a lesion of the adult central nervous system (CNS). Here, we identify Claudin k as a myelin-associated protein in zebrafish and determine its localization during development and adult optic nerve regeneration. We find Claudin k in subcellular compartments consistent with location in autotypic tight junctions of oligodendrocytes and myelinating Schwann cells. Expression starts in the hindbrain at 2 days (mRNA) and 3 days (protein) postfertilization and is maintained in adults. A newly generated claudin k:green fluorescent protein (GFP) reporter line allowed us to characterize oligodendrocytes in the adult retina that express Claudin k and olig2, but not P0 and uniquely only form loose wraps of membrane around axons. After a crush of the adult optic nerve, Claudin k protein levels were first reduced and then recovered within 4 weeks postlesion, concomitant with optic nerve myelin de- and regeneration. During optic nerve regeneration, oligodendrocytes, many of which were newly generated, repopulated the lesion site and exhibited increasing morphological complexity over time. Thus, Claudin k is a novel myelin-associated protein expressed by oligodendrocytes and Schwann cells from early stages of wrapping and myelin formation in zebrafish development and adult regeneration, suggesting important functions of the gene for myelin formation and maintenance. Our Claudin k antibodies and claudin k:GFP reporter line represent excellent ways to visualize oligodendrocyte and Schwann cell differentiation in vivo.
AU  - Münzel, E.J.*
AU  - Schaefer, K.*
AU  - Obirei, B.*
AU  - Kremmer, E.
AU  - Burton, E.A.*
AU  - Kuscha, V.*
AU  - Becker, C.G.*
AU  - Brösamle, C.*
AU  - Williams, A.*
AU  - Becker, T.*
C1  - 6683
C2  - 29120
SP  - 253-270
TI  - Claudin k is specifically expressed in cells that form myelin during development of the nervous system and regeneration of the optic nerve in adult zebrafish.
JO  - Glia
VL  - 60
IS  - 2
PB  - Wiley-Blackwell
PY  - 2012
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Glial cell line-derived neurotrophic factor (GDNF) enhances the survival of a variety of neurons, including photoreceptors (PR) in the retina. In contrast to most other GDNF receptive neurons, GDNF does, however, not exert its neuroprotective activity directly on PR neurons but transmits it indirectly by inducing expression of yet unknown neurotrophic factors in retinal Muller glial (RMG) cells. Genome-wide differential transcriptome analyses of GDNF-treated mouse retinas revealed 30 GDNF-induced transcripts containing a total of six genes coding for secreted molecules. Among them was (OPN), a secreted glycoprotein which was expressed in mouse RMG and secreted from primary mouse RMG in culture. Furthermore, OPN secretion was significantly upregulated on GDNF treatment of primary RMG. To validate, whether OPN could qualify as a neuroprotective factor for PR, we evaluated its potential neurotrophic activity on isolated PR in vitro as well as on retinal explants from the retinal degeneration 1 (Pde6b(rd1)) mouse mutant. OPN exerted a significant, positive survival effect on primary porcine PR cells in a concentration-dependent manner and induced activation of PI3K/Akt pro-survival pathway. Moreover, in retinal explant cultures from Pde6b(rd1) mice, OPN significantly reduced the percentage of apoptotic cells to levels comparable with that observed in explants from wild-type mice and led to survival of significantly more PR in long-term retinal explant cultures. Our findings suggest that RMG-derived OPN is a novel candidate protein that transmits part of the GDNF-induced neuroprotective activity of RMG to PR cells.
AU  - del Río, P.
AU  - Irmler, M.
AU  - Arango-González, B.*
AU  - Favor, J.
AU  - Bobe, C.
AU  - Bartsch, U.*
AU  - Vecino, E.*
AU  - Beckers, J.
AU  - Hauck, S.M.
AU  - Ueffing, M.
C1  - 5648
C2  - 28426
CY  - Malden, USA
SP  - 821-832
TI  - GDNF-induced osteopontin from Müller glial cells promotes photoreceptor survival in the Pde6brd1 mouse model of retinal degeneration.
JO  - Glia
VL  - 59
IS  - 5
PB  - Wiley-Blackwell
PY  - 2011
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Reactive gliosis is a well-established response to virtually every retinal disease. Autoimmune uveitis, a sight threatening disease, is characterized by recurrent relapses through autoaggressive T-cells. The purpose of this study was to assess retinal Müller glial cell function in equine recurrent uveitis (ERU), a spontaneous disease model resembling the human disease, by investigating membrane proteins implicated in ion and water homeostasis. We found that Kir2.1 was highly expressed in diseased retinas, whereas Kir4.1 was downregulated in comparison to controls. Distribution of Kir2.1 appeared Müller cell associated in controls, whereas staining of cell somata in the inner nuclear layer was observed in uveitis. In contrast to other subunits, Kir4.1 was evenly expressed along equine Müller cells, whereas in ERU, Kir4.1 almost disappeared from Müller cells. Hence, we suggest a different mechanism for potassium buffering in the avascular equine retina and, moreover, an impairment in uveitis. Uveitic retinas showed significantly increased expression of AQP4 as well as a displaced expression from Müller cells in healthy specimens to an intense circular expression pattern in the outer nuclear layer in ERU cases. Most interestingly, we detected the aquaporin family member protein AQP5 to be expressed in Müller cells with strong enrichments in Müller cell secondary processes. This finding indicates that fluid regulation within the equine retina may be achieved by an additional aquaporin. Furthermore, AQP5 was significantly decreased in uveitis. We conclude that the Müller cell response in autoimmune uveitis implies considerable changes in its potassium and water physiology.
AU  - Eberhardt, C.*
AU  - Amann, B.*
AU  - Feuchtinger, A.
AU  - Hauck, S.M.
AU  - Deeg, C.A.*
C1  - 6452
C2  - 28706
SP  - 697-707
TI  - Differential expression of inwardly rectifying K+ channels and aquaporins 4 and 5 in autoimmune uveitis indicates misbalance in Müller glial cell-dependent ion and water homeostasis.
JO  - Glia
VL  - 59
IS  - 5
PB  - Wiley-Blackwell
PY  - 2011
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The adult brain parenchyma contains a widespread population of progenitors generating different cells of the oligodendrocyte lineage such as NG2+ cells and some mature oligodendrocytes. However, it is still largely unknown how proliferation and lineage decisions of these progenitors are regulated. Here, we first characterized the cell cycle length, proliferative fraction, and progeny of dividing cells in the adult cerebral cortex and then compared these proliferation characteristics after two distinct stimuli, invasive acute brain injury and increased physiological activity by voluntary physical exercise. Our data show that adult parenchymal progenitors have a very long cell cycle due to an extended G1 phase, many of them can divide at least twice and only a limited proportion of the progeny differentiates into mature oligodendrocytes. After stab wound injury, however, many of these progenitors re-enter the cell cycle very fast, suggesting that the normally long G1 phase is subject to regulation and can be abruptly shortened. In striking contrast, voluntary physical exercise shows the opposite effect with increased exit of the cell cycle followed by an enhanced and fast differentiation into mature oligodendrocytes. Taken together, our data demonstrate that the endogenous population of adult brain parenchymal progenitors is subject to profound modulation by environmental stimuli in both directions, either faster proliferation or faster differentiation.
AU  - Simon, C.
AU  - Götz, M.
AU  - Dimou, L.
C1  - 6130
C2  - 28360
SP  - 869-881
TI  - Progenitors in the adult cerebral cortex: Cell cycle properties and regulation by physiological stimuli and injury.
JO  - Glia
VL  - 59
IS  - 6
PB  - Wiley-Blackwell
PY  - 2011
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The zebrafish has become a new model for adult neurogenesis, owing to its abundant neurogenic areas in most brain subdivisions. Radial glia-like cells, actively proliferating cells, and label-retaining progenitors have been described in these areas. In the telencephalon, this complexity is enhanced by an organization of the ventricular zone (VZ) in fast and slow-dividing domains, suggesting the existence of heterogeneous progenitor types. In this work, we studied the expression of various transgenic or immunocytochemical markers for glial cells (gfap:gfp, cyp19a1b:gfp, BLBP, and S100beta), progenitors (nestin:gfp and Sox2), and neuroblasts (PSA-NCAM) in cycling progenitors of the adult zebrafish telencephalon (identified by expression of proliferating cell nuclear antigen (PCNA), MCM5, or bromodeoxyuridine incorporation). We demonstrate the existence of distinct populations of dividing cells at the adult telencephalic VZ. Progenitors of the overall slow-cycling domains express high levels of Sox2 and nestin:gfp as well as all glial markers tested. In contrast, domains with an overall fast division rate are characterized by low or missing expression of glial markers. PCNA-positive cells in fast domains further display a morphology distinct from radial glia and co-express PSA-NCAM, suggesting that they are early neuronal precursors. In addition, the VZ contains cycling progenitors that express neither glial markers nor nestin:gfp, but are positive for Sox2 and PSA-NCAM, identifying them as committed neuroblasts. On the basis of the marker gene expression and distinct cell morphologies, we propose a classification for the dividing cell states at the zebrafish adult telencephalic VZ.
AU  - März, M.*
AU  - Chapouton, P.
AU  - Diotel, N.*
AU  - Vaillant, C.*
AU  - Hesl, B.
AU  - Takamiya, M.*
AU  - Lam, C.S.*
AU  - Kah, O.*
AU  - Bally-Cuif, L.
AU  - Strähle, U.*
C1  - 2094
C2  - 27697
SP  - 870-888
TI  - Heterogeneity in progenitor cell subtypes in the ventricular zone of the zebrafish adult telencephalon.
JO  - Glia
VL  - 58
IS  - 7
PB  - Wiley-Blackwell
PY  - 2010
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Astrocytes play many pivotal roles in the adult brain, including their reaction to injury. A hallmark of astrocytes is the contact of their endfeet with the basement membrane surrounding blood vessels, but still relatively little is known about the signaling mediated at the contact site. Here, we examine the role of beta1-integrin at this interface by its conditional deletion using different Cre lines. Thereby, the protein was reduced only at postnatal stages either in both glia and neurons or specifically only in neurons. Strikingly, only the former resulted in reactive gliosis, with the hallmarks of reactive astrocytes comprising astrocyte hypertrophy and up-regulation of the intermediate filaments GFAP and vimentin as well as pericellular components, such as Tenascin-C and the DSD-1 proteoglycan. In addition, we also observed to a certain degree a non-cell autonomous activation of microglial cells after conditional beta1-integrin deletion. However, these reactive astrocytes did not divide, suggesting that the loss of beta1-integrin-mediated signaling is not sufficient to elicit proliferation of these cells as observed after brain injury. Interestingly, this partial reactive gliosis appeared in the absence of cell death and blood brain barrier disturbances. As these effects did not appear after neuron-specific deletion of beta1-integrin, we conclude that beta1-integrin-mediated signaling in astrocytes is required to promote their acquisition of a mature, nonreactive state. Alterations in beta1-integrin-mediated signaling may hence be implicated in eliciting specific aspects of reactive gliosis after injury.
AU  - Robel, S.
AU  - Mori, T.
AU  - Zoubaa, S.
AU  - Schlegel, J.
AU  - Sirko, S.*
AU  - Faissner, A.*
AU  - Goebbels, S.*
AU  - Dimou, L.*
AU  - Götz, M.
C1  - 2906
C2  - 26460
CY  - Hoboken, NJ
SP  - 1630-1647
TI  - Conditional deletion of β1-integrin in astroglia causes partial reactive gliosis.
JO  - Glia
VL  - 57
IS  - 15
PB  - Wiley-Blackwell
PY  - 2009
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - The floor plate (FP), a signaling center and a structure rich in radial glia-like cells, has been traditionally thought to be devoid of neurons and neuronal progenitors. However, in the midbrain, the FP contains neurons of the dopaminergic (DA) lineage that require contact with radial glia-like cells for their induction. We, therefore, decided to explore the interaction relationship between radial glia and neurons during DA neurogenesis. Taking advantage of a novel FP radial glia-like cell culture system and retroviruses, DA neurons were lineage traced in vitro. In utero BrdU pulse-chases extensively labeled the midbrain FP and traced DA neurons both in vivo and in FP cultures. Moreover, from E9.5 to E13.5 the midbrain FP contained dividing cells only in the most apical part of the neuroepithelium, in cells identified as radial glia-like cells. We, therefore, hypothesized that midbrain FP radial glia-like cells could be DA progenitors and tested our hypothesis in vivo. Lineage tracing of DA progenitors with EGFP in Tis21-EGFP knock-in mice, and genetic fate mapping in GLAST::CreERT2/ZEG mice identified the neuroepithelium of the midbrain FP, and specifically, GLAST+ radial glia-like cells as DA progenitors. Combined, our experiments support the concept that the midbrain FP differs from other FP regions and demonstrate that FP radial glia-like cells in the midbrain are neurogenic and give rise to midbrain DA neurons.
AU  - Bonilla, S.*
AU  - Hall, A.C.*
AU  - Pinto, L.
AU  - Attardo, A.
AU  - Götz, M.
AU  - Huttner, W.B.
AU  - Arenas, E.*
C1  - 3620
C2  - 25401
SP  - 809-820
TI  - Identification of midbrain floor plate radial glia-like cells as dopaminergic progenitors.
JO  - Glia
VL  - 56
IS  - 8
PB  - Wiley-Blackwell
PY  - 2008
SN  - 0894-1491
ER  - 

TY  - JOUR
AB  - Neurosteroids, such as progesterone, influence central nervous system development and function by regulating a broad spectrum of physiological processes. Here, we investigated membrane-initiated actions of progesterone in the retina and identified the membrane-associated progesterone receptor component 1 (PGRMC1). We found PGRMC1 expressed mainly in retinal Muller glia (RMG) and retinal pigment epithelium, and localized uniquely to microsomal and plasma membrane fractions. In RMG, membrane-impermeable progesterone conjugate induced calcium influx and subsequent phosphatidylinositol 3-kinase-mediated phosphorylation of PKC and ERK-1/2. Induction by progesterone also led to PKC-dependent activation of VEGF gene expression and protein synthesis, suggesting a contribution of membrane-initiated hormone effects to VEGF induced neovascularization within retina.
AU  - Swiatek-de Lange, M.
AU  - Stampfl, A.
AU  - Hauck, S.M.
AU  - Zischka, H.
AU  - Gloeckner, C.J.
AU  - Deeg, C.A.*
AU  - Ueffing, M.
C1  - 3526
C2  - 24444
SP  - 1061-1073
TI  - Membrane-initiated effects of progesterone on calcium dependent signaling and activation of VEGF gene expression in retinal glial cells.
JO  - Glia
VL  - 55
IS  - 10
PB  - Wiley-Blackwell
PY  - 2007
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Mori, T.
AU  - Tanaka, K.*
AU  - Buffo, A.
AU  - Wurst, W.
AU  - Kühn, R.
AU  - Götz, M.
C1  - 4534
C2  - 23646
SP  - 21-34
TI  - Inducible gene deletion in astroglia and radial glia-A valuable tool for functional and lineage analysis.
JO  - Glia
VL  - 54
PB  - Wiley
PY  - 2006
SN  - 0894-1491
ER  - 

TY  - JOUR
AU  - Hauck, S.M.
AU  - Suppmann, S.
AU  - Ueffing, M.
C1  - 10145
C2  - 21593
SP  - 251-263
TI  - Proteomic profiling of primary retinal müller glia cells reveals a shift in expression patterns upon adaption to in vitro conditions.
JO  - Glia
VL  - 44
PB  - Wiley
PY  - 2003
SN  - 0894-1491
ER  -