Selective regulation of axonal growth from developing hippocampal neurons by tumor necrosis factor superfamily member APRIL.
APRIL (A Proliferation-Inducing Ligand, TNFSF13) is a member of the tumor necrosis factor superfamily that regulates lymphocyte survival and activation and has been implicated in tumorigenesis and autoimmune diseases. Here we report the expression and first known activity of APRIL in the nervous system. APRIL and one of its receptors, BCMA (B-Cell Maturation Antigen, TNFRSF17), are expressed by hippocampal pyramidal cells of fetal and postnatal mice. In culture, these neurons secreted APRIL, and function-blocking antibodies to either APRIL or BCMA reduced axonal elongation. Recombinant APRIL enhanced axonal elongation, but did not influence dendrite elongation. The effect of APRIL on axon elongation was inhibited by anti-BCMA and the expression of a signaling-defective BCMA mutant in these neurons, suggesting that the axon growth-promoting effect of APRIL is mediated by BCMA. APRIL promoted phosphorylation and activation of ERK1, ERK2 and Akt and serine phosphorylation and inactivation of GSK-3β in cultured hippocampal pyramidal cells. Inhibition of MEK1/MEK2 (activators of ERK1/ERK2), PI3-kinase (activator of Akt) or Akt inhibited the axon growth-promoting action of APRIL, as did pharmacological activation of GSK-3β and the expression of a constitutively active form of GSK-3β. These findings suggest that APRIL promotes axon elongation by a mechanism that depends both on ERK signaling and PI3-kinase/Akt/GSK-3β signaling.
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom.
Catarina
C
Osório
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Americo Vespucio s/n, Isla de la Cartuja, 41092 Seville, Spain.
Pedro J
PJ
Chacón
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom.
Matthew
M
White
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom.
Lilian
L
Kisiswa
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom.
Sean
S
Wyatt
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Americo Vespucio s/n, Isla de la Cartuja, 41092 Seville, Spain.
Alfredo
A
Rodríguez-Tébar
School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom. Electronic address: daviesalun@cf.ac.uk.
Alun M
AM
Davies
D000818:Animals; D001369:Axons / Q000378:metabolism*; D053301:B-Cell Maturation Antigen / Q000378:metabolism; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D055495:Neurogenesis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism*
D053301:B-Cell Maturation Antigen; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C490176:Tnfrsf17 protein, mouse; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse
Axon; Hippocampal pyramidal cell; Tumor necrosis factor receptor superfamily; Tumor necrosis factor superfamily