Abstract
Extensive neuronal cell death during development is believed to be due to a limiting supply of neurotrophic factors.
In vitro
studies suggest that axon guidance molecules directly regulate neuronal survival, raising the possibility that they play a direct role in neuronal cell death
in vivo
. However, guidance errors may also influence survival indirectly due to loss of target-derived neurotrophic support. The role of guidance molecules in neuronal death
in vivo
has thus been difficult to decipher. Semaphorin3A, a repulsive guidance cue for sensory neurons, can induce sensory neuron death
in vitro
. Null mice studies of the Semaphorin3A coreceptors showed that guidance activity is mediated by PlexinA4, but PlexinA3 partially compensates in PlexinA4
−/−
mice. Here we demonstrate that both Plexins contribute to Sema3A-induced cell death
in vitro
, albeit in a different hierarchy. PlexinA3 is absolutely required, while PlexinA4 makes a smaller contribution to cell death. We found that PlexinA3
−/−
mice, which, unlike PlexinA4
−/−
mice, do not exhibit sensory axon patterning defects, show reduced neuronal apoptosis and an increased number of DRG neurons. Semaphorin3A involvement in neuronal death
in vivo
was demonstrated by a sensitization experiment using the proapoptotic effector
Bax
. Our results identify Plexins as mediators of Semaphorin-induced cell death
in vitro
, and provide the first evidence implicating Semaphorin/Plexin signaling in neuronal survival independent of its role in axon guidance. The results also support the idea that naturally occurring neuronal cell death reflects not only competition for target-derived trophic factors, but also the action of proapoptotic signaling via a Semaphorin/Plexin pathway.