Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus.
Neural stem cells (NSCs) in the adult hippocampus divide infrequently, and the molecules that modulate their quiescence are largely unknown. Here, we show that bone morphogenetic protein (BMP) signaling is active in hippocampal NSCs, downstream of BMPR-IA. BMPs reversibly diminish proliferation of cultured NSCs while maintaining their undifferentiated state. In vivo, acute blockade of BMP signaling in the hippocampus by intracerebral infusion of Noggin first recruits quiescent NSCs into the cycle and increases neurogenesis; subsequently, it leads to decreased stem cell division and depletion of precursors and newborn neurons. Consistently, selective ablation of Bmpr1a in hippocampal NSCs, or inactivation of BMP canonical signaling in conditional Smad4 knockout mice, transiently enhances proliferation but later leads to a reduced number of precursors, thereby limiting neuronal birth. BMPs are therefore required to balance NSC quiescence/proliferation and to prevent loss of the stem cell activity that supports continuous neurogenesis in the mature hippocampus.
Mira
Helena
H
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. helena.mira@uv.es
Andreu
Zoraida
Z
Suh
Hoonkyo
H
Lie
D Chichung
DC
Jessberger
Sebastian
S
Consiglio
Antonella
A
San Emeterio
Juana
J
Hortigüela
Rafael
R
Marqués-Torrejón
María Angeles
MA
Nakashima
Kinichi
K
Colak
Dilek
D
Götz
Magdalena
M
Fariñas
Isabel
I
Gage
Fred H
FH
D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D005434:Flow Cytometry; D005822:Genetic Vectors; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D016086:Lentivirus; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000099176:Noggin Protein
D052005:Bone Morphogenetic Protein Receptors, Type I; D002352:Carrier Proteins; D051901:Smad4 Protein; D000099176:Noggin Protein