Nuclear orphan receptor TLX induces Oct-3/4 for the survival and maintenance of adult hippocampal progenitors upon hypoxia.
Hypoxia promotes neural stem cell proliferation, the mechanism of which is poorly understood. Here, we have identified the nuclear orphan receptor TLX as a mediator for proliferation and pluripotency of neural progenitors upon hypoxia. We found an enhanced early protein expression of TLX under hypoxia potentiating sustained proliferation of neural progenitors. Moreover, TLX induction upon hypoxia in differentiating conditions leads to proliferation and a stem cell-like phenotype, along with coexpression of neural stem cell markers. Following hypoxia, TLX is recruited to the Oct-3/4 proximal promoter, augmenting the gene transcription and promoting progenitor proliferation and pluripotency. Knockdown of Oct-3/4 significantly reduced TLX-mediated proliferation, highlighting their interdependence in regulating the progenitor pool. Additionally, TLX synergizes with basic FGF to sustain cell viability upon hypoxia, since the knockdown of TLX along with the withdrawal of growth factor results in cell death. This can be attributed to the activation of Akt signaling pathway by TLX, the depletion of which results in reduced proliferation of progenitor cells. Cumulatively, the data presented here demonstrate a new role for TLX in neural stem cell proliferation and pluripotency upon hypoxia.
Institute of Biomedicine, Department of Medical Chemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
Pavithra Lakshminarasimhan
PL
Chavali
Ravi Kanth Rao
RK
Saini
Yoshiki
Y
Matsumoto
Hans
H
Ågren
Keiko
K
Funa
D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C088601:NR2E1 protein, human; C490258:Nr2e1 protein, mouse; D050814:Octamer Transcription Factor-3; D057093:Orphan Nuclear Receptors; C494173:POU5F1 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D051057:Proto-Oncogene Proteins c-akt