Selective regulation of axonal growth from developing hippocampal neurons by tumor necrosis factor superfamily member APRIL.
Bottom Line: 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.APRIL promoted phosphorylation and activation of ERK1, ERK2 and Akt and serine phosphorylation and inactivation of GSK-3β in cultured hippocampal pyramidal cells.
Affiliation: School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom.Show MeSH
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Mentions: To test whether PI-3 kinase signaling contributes to APRIL-promoted axon growth, we first examined whether the selective PI-3 kinase inhibitor LY294002 (Vlahos et al., 1994) was able to prevent the APRIL-promoted axon elongation. In these experiments, the neurons were transfected with a GFP plasmid 2 days after plating and were pretreated for 2 h with LY294002 before adding APRIL to the culture medium and quantifying axon length 18 h later. Whereas axon length in cultures that received LY294002 alone was not significantly different from that in control cultures, LY294002 completely prevented the axon growth-enhancing effect of APRIL (Fig. 6A and B). To confirm the results of these pharmacological experiments, we transfected pyramidal cells with a construct that expresses both GFP and a dominant-negative form of the p85α regulatory subunit of PI-3 kinase that lacks the binding domain for the p110 catalytic subunit. The p85α mutant had a small, significant effect on axon extension from neurons not exposed to exogenous APRIL, and completely eliminated the axon growth-enhancing effect of exogenous APRIL (Fig. 6C and D). Taken together, these results suggest that PI3-kinase signaling is required for the effect of APRIL on axon growth.
Affiliation: School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AT Wales, United Kingdom.