The lateral ventricle wall of the adult mouse brain, labelled with EphA7 (green), ephrin-A2 (red) and a nuclear stain (blue). Image courtesy of J. Frisén, Karolinska Institute, Sweden.

The number of cells in an organ is mainly controlled at the level of proliferation and apoptosis by mitogens and trophic factors. Now, Holmberg and colleagues have identified a novel mechanism whereby the number of neurons in the adult brain is negatively regulated by EphA7-induced ephrin-A2 reverse signalling in neural progenitors.

Ephrins and their Eph tyrosine kinase receptors are important regulators of developmental processes such as axon guidance, cell migration and synapse formation, but their roles in the adult organism are not clear. In the adult mouse brain, ephrin-A2 and EphA7 are expressed in a complementary and mutually exclusive pattern in the lateral wall of the lateral ventricles — one of the neural stem cell niches in the adult brain that can give rise to neurons.

Perturbation of ephrin-A2–EphA7 signalling by infusion of the soluble form of either protein increases the number of proliferating cells in the lateral ventricular wall. In mice that lack ephrin-A2 or EphA7, cells in the neural stem cell niche proliferate more and have a shorter cell cycle, which indicates that ephrin-A2 and EphA7 are negative regulators of proliferation.

Ephrins and Ephs can mediate bi-directional signalling — either through Eph receptors (forward signalling) or through membrane-bound ephrin ligands (reverse signalling). But which signalling pathway is important for neurogenesis? In ephrin-2A-knockout mice, EphA7-expressing cells in the lateral ventricular wall remain quiescent; whereas cells that express progenitor markers — which would normally be co-expressed with ephrin-A2 in wild-type animals — show increased proliferative activity. In addition, overexpression of a truncated EphA7 receptor in wild-type neurospheres leads to a significant decrease in proliferation — an effect that is not seen in the absence of ephrin-A2. Holmberg et al. conclude that the negative regulation of proliferation by EphA7 and ephrin-A2 is mediated by reverse signalling.

The majority of the neurons that are born in the lateral ventricle wall migrate to the olfactory bulb. In ephrin-A2-knockout mice, there is an increased number of newborn cells in the adult olfactory bulb, which indicates that the proliferative activity early in the lineage is an important determinant of the number of neurons that integrate the target tissue. Disruption of the EphA7–ephrin-A2 reverse signalling by infusion of soluble ephrin-A2 disinhibits proliferation and results in increased neurogenesis in the adult brain.

It will be important to determine whether there is a similar mechanism in other stem cell populations in which ephrins and Ephs are also expressed. Manipulating the ephrin–Eph signalling could be a potential therapeutic strategy in regenerative medicine and cancer treatment.