Signaling through BMPR-IA Regulates Quiescence and Long-Term Activity of Neural Stem Cells in the Adult Hippocampus

Cell Stem Cell, Volume 7, Issue 1, 78-89, 2 July 2010 | Copyright © 2010 Elsevier Inc. All rights reserved. | 10.1016/j.stem.2010.04.016
Signaling through BMPR-IA Regulates Quiescence and Long-Term Activity of Neural Stem Cells in the Adult Hippocampus
Helena Mira, Zoraida Andreu, Hoonkyo Suh, D. Chichung Lie, Sebastian Jessberger, Antonella Consiglio, Juana San Emeterio, Rafael Hortigüela, María Ángeles Marqués-Torrejón, Kinichi Nakashima, Dilek Colak, Magdalena Götz, Isabel Fariñas, Fred H. Gage

Highlights
BMP signaling is active in nondividing adult hippocampal NSCs and in neurons
BMP treatment reversibly increases quiescence of cultured adult NSCs
In vivo, blocking BMPs recruits quiescent NSCs and enhances neurogenesis
This transient increase in NSC proliferation impairs subsequent stem cell activity

Summary
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.

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