Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 4; pp. 1317 - 1322
• Main Authors: Gómez-Gaviro, María Victoria, Scott, Charlotte E, Sesay, Abdul K, Matheu, Ander, Booth, Sarah, Galichet, Christophe, Lovell-Badge, Robin
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24-01-2012; National Acad Sciences
• Subjects: adults; Animals; antibodies; Betacellulin; Biological Sciences; Blood vessels; Blotting, Western; Brain; Cell culture; Cell growth; Cell Line; Cell Proliferation; Cells; Dentate gyrus; Differentiation; Endothelial cells; Endothelial Cells - metabolism; Epidermal growth factor; ErbB Receptors - metabolism; ErbB-2 protein; Hepatocytes; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Lateral ventricles; Mice; Microscopy, Confocal; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - physiology; Neuroblasts; Neurogenesis; Neurogenesis - physiology; Neurons; niches; Olfactory bulb; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Receptor, ErbB-4; Receptors; Rodents; Signal Transduction - physiology; Stem cells; subventricular zone; Ventricles (cerebral)
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1016199109

Neural stem cells (NSCs) reside in specialized niches in the adult mammalian brain, including the subventricular zone and the dentate gyrus, which act to control NSC behavior. Among other cell types within these niches, NSCs are found in close proximity to blood vessels. We carried out an analysis of the interaction between endothelial cells and NSCs, and show that betacellulin (BTC), a member of the EGF family and one of several signaling molecules made by the former, induces NSC proliferation and prevents spontaneous differentiation in culture. When infused into the lateral ventricle, BTC induces expansion of NSCs and neuroblasts, and promotes neurogenesis in the olfactory bulb and dentate gyrus, whereas specific blocking antibodies reduce the number of stem/progenitor cells. BTC-null mice are less able to regenerate neuroblast numbers compared with WT littermates following depletion of proliferating cells using cytosine-β-D-arabinofuranoside. BTC acts via both the EGF receptor, located on NSCs, and ErbB4, located on neuroblasts, with the latter explaining why its effects are distinct from those of EGF itself. Our results suggest that BTC could be a good candidate to aid regenerative therapies.