A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation.
BACKGROUND
A converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 (sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling.


RESULTS
Here, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus.


CONCLUSIONS
Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.
Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing, 100084, P.R. China.|Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Jiaqi
J
Sun
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Present Address: Broad CIRM Center and Department of Stem Cell Biology and Regenerative Medicine, Zilkha Neurogenetic Institute, University of Southern California Keck School of Medicine, Los Angeles, CA, 90033, USA.
Michael A
MA
Bonaguidi
Department of Neurologic Surgery, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
Heechul
H
Jun
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Present Address: Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.
Junjie U
JU
Guo
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Gerald J
GJ
Sun
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Brett
B
Will
Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
Zhengang
Z
Yang
Department of Neurologic Surgery, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
Mi-Hyeon
MH
Jang
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Hongjun
H
Song
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. gming1@jhmi.edu.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. gming1@jhmi.edu.|The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. gming1@jhmi.edu.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. gming1@jhmi.edu.
Guo-li
GL
Ming
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Kimberly M
KM
Christian
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D009457:Neuroglia / Q000166:cytology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000099274:Frizzled-Related Proteins
D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D000099274:Frizzled-Related Proteins