TY  - JOUR
A1  - Kumar, Praveen
A1  - Naumann, Ulrike
A1  - Aigner, Ludwig
A1  - Wischhusen, Joerg
A1  - Beier, Christoph P
A1  - Beier, Dagmar
T1  - Impaired TGF-β induced growth inhibition contributes to the increased proliferation rate of neural stem cells harboring mutant p53
JF  - American Journal of Cancer Research
N2  - Gliomas have been classified according to their histological properties. However, their respective cells of origin are still unknown. Neural progenitor cells (NPC) from the subventricular zone (SVZ) can initiate tumors in murine models of glioma and are likely cells of origin in the human disease. In both, p53 signaling is often functionally impaired which may contribute to tumor formation. Also, TGF-beta, which under physiological conditions exerts a strong control on the proliferation of NPCs in the SVZ, is a potent mitogen on glioma cells. Here, we approach on the crosstalk between p53 and TGF-beta by loss of function experiments using NPCs derived from p53 mutant mice, as well as pharmacological inhibition of TGF-beta signaling using TGF-beta receptor inhibitors. NPC derived from p53 mutant mice showed increased clonogenicity and more rapid proliferation than their wildtype counterparts. Further, NPC derived from p53\(^{mut/mut}\) mice were insensitive to TGF-beta induced growth arrest. Still, the canonical TGF-beta signaling pathway remained functional in the absence of p53 signaling and expression of key proteins as well as phosphorylation and nuclear translocation of SMAD2 were unaltered. TGF-beta-induced p21 expression could, in contrast, only be detected in p53\(^{wt/wt}\) but not in p53\(^{mut/mut}\) NPC. Conversely, inhibition of TGF-beta signaling using SB431542 increased proliferation of p53\(^{wt/wt}\) but not of p53\(^{mut/mut}\) NPC. In conclusion, our data suggest that the TGF-beta induced growth arrest in NPC depends on functional p53. Mutational inactivation of p53 hence contributes to increased proliferation of NPC and likely to the formation of hyperplasia of the SVZ observed in p53 deficient mice in vivo.
KW  - mouse brain
KW  - tumors
KW  - cancer
KW  - TGF-beta
KW  - glioblastoma stem cell
KW  - pathways
KW  - expression
KW  - astrocytoma
KW  - glioblastoma
KW  - transforming growth factor-beta-1
KW  - neurogenesis
KW  - gliomas
KW  - neural stem cell
KW  - p53
KW  - subventricular zone
KW  - premalignant lesion
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144262
VL  - 5
IS  - 11
ER  - 
TY  - JOUR
A1  - Beyer, Felix
A1  - Jadasz, Janusz
A1  - Samper Agrelo, Iria
A1  - Schira‐Heinen, Jessica
A1  - Groh, Janos
A1  - Manousi, Anastasia
A1  - Bütermann, Christine
A1  - Estrada, Veronica
A1  - Reiche, Laura
A1  - Cantone, Martina
A1  - Vera, Julio
A1  - Viganò, Francesca
A1  - Dimou, Leda
A1  - Müller, Hans Werner
A1  - Hartung, Hans‐Peter
A1  - Küry, Patrick
T1  - Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system
JF  - Glia
N2  - Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell‐dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.
KW  - glial fate modulation
KW  - myelin
KW  - neural stem cell
KW  - p57kip2
KW  - regional heterogeneity
KW  - spinal cord injury
KW  - transplantation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218566
VL  - 68
IS  - 2
SP  - 393
EP  - 406
ER  -