TY  - JOUR
AU  - Khan, Dilaware
AU  - Bock, Dagmar
AU  - Liu, Hai-Kun
AU  - Muhammad, Sajjad
TI  - Tlx Promotes Stroke-Induced Neurogenesis and Neuronal Repair in Young and Aged Mice.
JO  - International journal of molecular sciences
VL  - 25
IS  - 22
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2024-02454
SP  - 12440
PY  - 2024
N1  - DKFZ-ZMBH Alliance
AB  - Stroke is one of the leading causes of chronic disability in humans. It has been proposed that the endogenous neural stem/progenitor cells generate new neurons in the damaged area. Still, the contribution of these cells is negligible because a low number of newborn mature neurons are formed. Tlx conventional knock-out mice, Tlx-CreERT2 mice, and Tlx-overexpressing (Tlx-OE) mice were specifically chosen for their unique genetic characteristics, which were crucial for the experiments. Permanent and transient middle cerebral artery occlusion was used to induce stroke in the mice. Immunostainings for doublecortin and GFP/BrdU/NeuN were performed to study neurogenesis and fate mapping. The rotarod test was performed to assess motor deficits. Here, we show that stroke-induced neurogenesis is dramatically increased with the additional expression of two copies of the nuclear receptor-coding gene tailless (Tlx, also known as Nr2e1), which has been shown to be a master regulator of subventricular zone (SVZ) neural stem cells (NSCs). We show that Tlx expression is upregulated after stroke, and stroke-induced neurogenesis is blocked when Tlx is inactivated. Tlx overexpression in NSCs leads to massive induction of neurogenesis via stroke. More newborn mature neurons are formed in Tlx-overexpressing mice, leading to improved coordination and motor function recovery. Most importantly, we also demonstrate that this process is sustained in aged mice, where stroke-induced neurogenesis is nearly undetectable in wild-type animals. This study provides the first stem cell-specific genetic evidence that endogenous NSCs can be exploited by manipulating their master regulator, Tlx, and thus suggests a novel therapeutic strategy for neuronal repair.
KW  - Animals
KW  - Neurogenesis
KW  - Mice
KW  - Neural Stem Cells: metabolism
KW  - Neural Stem Cells: cytology
KW  - Stroke: metabolism
KW  - Stroke: pathology
KW  - Neurons: metabolism
KW  - Receptors, Cytoplasmic and Nuclear: metabolism
KW  - Receptors, Cytoplasmic and Nuclear: genetics
KW  - Aging: metabolism
KW  - Mice, Knockout
KW  - Male
KW  - Mice, Inbred C57BL
KW  - Infarction, Middle Cerebral Artery: metabolism
KW  - Infarction, Middle Cerebral Artery: pathology
KW  - Tlx (Other)
KW  - adult neurogenesis (Other)
KW  - neural stem cells (Other)
KW  - stroke (Other)
KW  - Nr2e1 protein, mouse (NLM Chemicals)
KW  - Receptors, Cytoplasmic and Nuclear (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39596503
C2  - pmc:PMC11594625
DO  - DOI:10.3390/ijms252212440
UR  - https://inrepo02.dkfz.de/record/294721
ER  -