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

Abstract

The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (PI3K) in the nervous system are unknown. Whereas most PI3Ks have a broad tissue distribution, the tyrosine kinase-linked p110δ isoform has previously been shown to be enriched in leukocytes. Here we report that p110δ is also highly expressed in the nervous system. Inactivation of p110δ 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 p110δ activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110δ 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 p110δ, suggesting a key role of RhoA in p110δ signaling in neurons. Our data identify p110δ as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.

Effects of Isoform-selective Phosphatidylinositol 3-Kinase Inhibitors on Osteoclasts

“…PI3K signaling might initiate osteoclast spreading through interactions with other signaling pathways, including Rho, Rac, and Cdc42. In keeping with this idea, RhoA and Rac have been shown to be regulated negatively and positively by PI3K␦, respectively (15,39). Consistent with our findings, others have shown acute morphological contraction in macrophages upon PI3K␦ inactivation observed in parallel with decreased Rac activity and increased Rho activity (15).…”

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…Our study is in good agreement with other studies pointing to a key role of microglial TNF in early-phase inflammation in the CNS 13 . Our in vitro studies also highlight the presence of PI3Kd in neurons 28 but their role in TNF secretion could not be tested because secreted TNF was not detected by our assay in neuronal cultures exposed to either GD or LPS. The role played by PI3Kd in neurons will therefore require further investigation.…”

“…In vitro, PI3Kd is not detectable by immunocytochemistry in astrocytes but is present in neurons 28 and microglia in which it appears concentrated at the perinuclear Golgi 18 (Fig. 1a).…”

“…To recapitulate reperfusion in ischaemic stroke in vivo, we induced transient middle cerebral artery occlusion (tMCAO) 28,[33][34][35] in wild-type and p110d D910A/D910A mice, followed by 24-72 h reperfusion (Fig. 4a-c).…”

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy

“…PIK3CD is the predominant p110 catalytic subunit expressed in B lymphocytes (30) and high levels of expression are also reported in the embryonic mouse nervous system (31). Interestingly, PIK3CD associates in vitro, nonselectively with p85 regulatory subunits (25) and targeted deletion of the PIK3CD gene in mice produces compensatory changes in the p85 and p55 regulatory genes (32).…”