PI3K/Akt and ERK/MAPK Signaling Promote Different Aspects of Neuron Survival and Axonal Regrowth Following Rat Facial Nerve Axotomy
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The ERK/MAPK and PI3K/Akt signaling pathways play important role in neuronal survival and axonal regeneration after peripheral nerve injury. However, the relative importance and degree of functional overlap of the two pathways are still debated due to lack of in-vivo data. We used rats which underwent a facial nerve axotomy, and examined subsequent ERK/MAPK and PI3K/Akt signaling activity by quantifying phosphorylation of ERK and Akt. We also assessed the survival rate of facial neurons, number of regenerated axons, and the length of axonal regrowth in axotomized animals treated with an inhibitor of ERK/MAPK (U0126) or PI3K/Akt (LY294002) phosphorylation, or with vehicle. Axotomy increased phosphorylation of ERK and Akt in the facial nucleus 7 days after injury. The inhibition of ERK phosphorylation significantly reduced the length of regenerated axons, but not the other parameters. Inhibition of Akt phosphorylation significantly reduced the survival rate of facial neurons and the number of new axons, as well as the length of regenerated axons. The results indicate that facial nerve injury activates the ERK/MAPK and PI3K/Akt signaling pathways in the facial nerve nucleus and its axons. However, the pathways promoted aspects of regeneration with only slight overlap: PI3K/Akt signaling improved the survival of neurons, as well as axonal growth and branching, whereas ERK/MAPK signaling promoted only axonal extension.
KeywordsCranial nerve seven Axonal regeneration Kinase Neurite extension Neuron survival
Funding was provided by National Natural Science Foundation of China (Grant No. 30872898) and Beijing Municipal Natural Science Foundation (Grant No. 7132173).
- 8.Obata K, Yamanaka H, Dai Y, Tachibana T, Fukuoka T, Tokunaga A, Yoshikawa H, Noguchi K (2003) Differential activation of extracellular signal-regulated protein kinase in primary afferent neurons regulates brain-derived neurotrophic factor expression after peripheral inflammation and nerve injury. J Neurosci 23(10):4117–4126PubMedGoogle Scholar
- 9.Orike N, Middleton G, Borthwick E, Buchman V, Cowen T, Davies AM (2001) Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons. J Cell Biol 154(5):995–1005. doi: 10.1083/jcb.200101068 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Yamazaki T, Sabit H, Oya T, Ishii Y, Hamashima T, Tokunaga A, Ishizawa S, Jie S, Kurashige Y, Matsushima T, Furuta I, Noguchi M, Sasahara M (2009) Activation of MAP kinases, Akt and PDGF receptors in injured peripheral nerves. J Peripher Nerv Syst 14(3):165–176. doi: 10.1111/j.1529-8027.2009.00228.x CrossRefPubMedGoogle Scholar
- 20.Zhou X, Rodriguez WI, Casillas RA, Ma V, Tam J, Hu Z, Lelievre V, Chao A, Waschek JA (1999) Axotomy-induced changes in pituitary adenylate cyclase activating polypeptide (PACAP) and PACAP receptor gene expression in the adult rat facial motor nucleus. J Neurosci Res 57(6):953–961CrossRefPubMedGoogle Scholar
- 25.Heumann R, Goemans C, Bartsch D, Lingenhohl K, Waldmeier PC, Hengerer B, Allegrini PR, Schellander K, Wagner EF, Arendt T, Kamdem RH, Obst-Pernberg K, Narz F, Wahle P, Berns H (2000) Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration. J Cell Biol 151(7):1537–1548CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Skaper SD, Floreani M, Negro A, Facci L, Giusti P (1998) Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway. J Neurochem 70(5):1859–1868CrossRefPubMedGoogle Scholar
- 37.Traverse S, Gomez N, Paterson H, Marshall C, Cohen P (1992) Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J 288(Pt 2):351–355CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S, Rosenberg LH, Collins MJ, Harrisingh MC, White IJ, Woodhoo A, Lloyd AC (2012) A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73(4):729–742. doi: 10.1016/j.neuron.2011.11.031 CrossRefPubMedGoogle Scholar