CRH Promotes the Neurogenic Activity of Neural Stem Cells in the Adult Hippocampus
Yassemi Koutmani,
Ioannis A. Gampierakis,
Alexia Polissidis,
Methodios Ximerakis,
Paraskevi N. Koutsoudaki,
Alexandros Polyzos,
George Agrogiannis,
Sevasti Karaliota,
Dimitra Thomaidou,
Lee L. Rubin,
Panagiotis K. Politis,
Katia P. Karalis
Affiliations
Yassemi Koutmani
Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Corresponding author
Ioannis A. Gampierakis
Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
Alexia Polissidis
Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
Methodios Ximerakis
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
Paraskevi N. Koutsoudaki
Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens 11521, Greece
Alexandros Polyzos
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
George Agrogiannis
Department of Pathology, University of Athens Medical School, Athens 11527, Greece
Sevasti Karaliota
Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
Dimitra Thomaidou
Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens 11521, Greece
Lee L. Rubin
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Panagiotis K. Politis
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
Katia P. Karalis
Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece; Endocrine Division, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Emulate, Inc., Boston, MA 02210, USA; Corresponding author
Summary: Local cues in the adult neurogenic niches dynamically regulate homeostasis in neural stem cells, whereas their identity and associated molecular mechanisms remain poorly understood. Here, we show that corticotropin-releasing hormone (CRH), the major mediator of mammalian stress response and a key neuromodulator in the adult brain, is necessary for hippocampal neural stem cell (hiNSC) activity under physiological conditions. In particular, we demonstrate functionality of the CRH/CRH receptor (CRHR) system in mouse hiNSCs and conserved expression in humans. Most important, we show that genetic deficiency of CRH impairs hippocampal neurogenesis, affects spatial memory, and compromises hiNSCs’ responsiveness to environmental stimuli. These deficits have been partially restored by virus-mediated CRH expression. Additionally, we provide evidence that local disruption of the CRH/CRHR system reduces neurogenesis, while exposure of adult hiNSCs to CRH promotes neurogenic activity via BMP4 suppression. Our findings suggest a critical role of CRH in adult neurogenesis, independently of its stress-related systemic function. : Koutmani et al. report that the major stress mediator CRH directly promotes adult hippocampal neural stem cell activity under physiological conditions, through a BMP4-mediated mechanism. They also show conserved expression of the CRH/CRHR system in humans. Their findings suggest a stress-independent physiological role of CRH. Keywords: corticotropin-releasing hormone, CRH, CRF, adult neurogenesis, stem cells, BMP4, enriched environment, exercise, stress, hippocampus
