Expression and function of APRIL and GDF-5 in the developing hippocampus

Abstract

Neurite size and morphology are key determinants of the functional properties of neurons. In this thesis, it is described for the first time the expression of APRIL (A Proliferation-Inducing Ligand, TNFSF13) in the nervous system. APRIL is a member of the tumour necrosis factor superfamily and one of its receptors BCMA (B-Cell Maturation Antigen, TNFRSF17) are coexpressed in pyramidal neurons throughout the fetal and postnatal mouse hippocampus. The effect of APRIL on axon elongation is inhibited by the expression of a truncated BCMA receptor in the neurons, suggesting that BCMA mediates this effect. APRIL promotes rapid phosphorylation of ERK1/2, Akt and GSK-3β in cultured pyramidal neurons, and pharmacological inhibition of either MEK1/2 or PI3K, upstream activators of ERK1/2 and Akt/GSK-3β signalling, respectively, completely inhibits the axon growth-promoting action of APRIL. These findings reveal that APRIL selectively enhances axon growth from developing hippocampal pyramidal neurons by a mechanism that depends on BCMA and activation of ERK1/2 and Akt/GSK-3β signalling. In this thesis, it is also shown that GDF-5 (growth-differentiation factor 5), a member of the transforming growth factor-β superfamily with a wellcharacterized role in limb morphogenesis, is a key regulator of the growth and elaboration of pyramidal neuron dendrites in the developing hippocampus. Pyramidal neurons co-express GDF-5 and its preferred receptors bone morphogenetic protein receptor-IB and bone morphogenetic protein receptor-II during development. In culture, GDF-5 substantially increased dendrite, but not axon, elongation from these neurons by a mechanism that depends activation of Smads1/5/8 and upregulation of the Hes5 transcription factor. In vivo, the apical and basal dendritic arbors of pyramidal neurons throughout the hippocampus were very markedly stunted in both homozygous and heterozygous Gdf-5 null mutants, indicating that dendrite size and complexity are exquisitely sensitive to the level of endogenous GDF-5 synthesi