Neuroglobin, the third mammalian
globin with a hexa-coordinated
heme, exists predominantly in neurons of the brain.
Neuroglobin plays an important role in neuronal death upon
ischemia and oxidative stress. The physiological function of
neuroglobin remains unclear. Here, we report a novel function of
neuroglobin in neurite development. Knocking-down
neuroglobin exhibited a prominent neurite-deficient phenotype in mouse
neuroblastoma N2a cells. Silencing
neuroglobin prevented neurite outgrowth, while ectopic expression of
neuroglobin but not homologous
cytoglobin promoted neurite outgrowth of N2a cells upon serum withdrawal. In primary cultured rat cerebral cortical neurons,
neuroglobin was upregulated and preferentially distributed in neurites during neuronal development. Overexpression of
neuroglobin but not
cytoglobin in cultured cortical neurons promoted axonal outgrowth, while knocking-down of
neuroglobin retarded axonal outgrowth.
Neuroglobin overexpression suppressed
phosphatase and
tensin homolog (PTEN) but increased Akt phosphorylation during neurite induction. Bimolecular fluorescence complementation and
glutathione S-transferase pull-down assays revealed that
neuroglobin and various mutants (E53Q, E118Q, K119N, H64A, H64L, and Y44D) bound with Akt and PTEN differentially.
Neuroglobin E53Q showed a prominent reduced PTEN binding but increased Akt binding, resulting in decreased p-PTEN, increased p-Akt, and increased neurite length. Taken together, we demonstrate a critical role of
neuroglobin in neuritogenesis or development via interacting with PTEN and Akt differentially to activate
phosphatidylinositol 3-kinase/Akt pathway, providing potential therapeutic applications of
neuroglobin for axonopathy in neurological diseases.