Control of Axonal Growth and Regeneration of Sensory Neurons by the p110δ PI 3-Kinase

The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (P13K) in the nervous system are unknown. Whereas most P13Ks have a broad tissue distribution, the tyrosine kinase-linked p110 delta isoform has previously been shown to be enriched in leukocytes. Here we report that p110 delta is also highly expressed in the nervous system. Inactivation of p110 delta in mice did not affect gross neuronal development but led to an increased vulnerability of dorsal root ganglia neurons to exhibit growth cone collapse and decreases in axonal extension. Loss of p110 delta activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110 delta inactivation resulted in reduced neuronal signaling through the Akt protein kinase, and increased activity of the small GTPase RhoA. Pharmacological inhibition of ROCK, a downstream effector of RhoA, restored axonal extension defects in neurons with inactive p110 delta, suggesting a key role of RhoA in p110 delta signaling in neurons. Our data identify p110 delta as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.