Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis.
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.
Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom. vgomez@recava.com
María Victoria
MV
Gómez-Gaviro
Charlotte E
CE
Scott
Abdul K
AK
Sesay
Ander
A
Matheu
Sarah
S
Booth
Christophe
C
Galichet
Robin
R
Lovell-Badge
D000818:Animals; D066259:Betacellulin; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000502:physiology*
C587851:BTC protein, human; D066259:Betacellulin; C587852:Btc protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4