Suchergebnisse

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 ; This work was supported by the Wellcome Trust (grant number 085984) to AMD and Proyecto de Excelencia of the Regional Government of Andalussia (grant number P10-CVI-6740) to AR. CO was a recipient of Fundacao para a Ciencia e a Tecnologia PhD grant. PC was a recipient of a 'Sara Borrell' Postdoctoral Fellowship from the National Institute of Health 'Carlos III', Spain (grant number CD08/ 00078). ; Peer Reviewed

Dendrite size and morphology are key determinants of the functional properties of neurons. Here, we show that growth differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) subclass of the transforming growth factor β superfamily with a wellcharacterised role in limb morphogenesis, is a key regulator of the growth and elaboration of pyramidal cell dendrites in the developing hippocampus. Pyramidal cells co-express GDF5 and its preferred receptors, BMP receptor 1B and BMP receptor 2, during development. In culture, GDF5 substantially increased dendrite, but not axon, elongation from these neurons by a mechanism that depends on activation of SMADs 1/5/8 and upregulation of the transcription factor HES5. In vivo, the apical and basal dendritic arbours of pyramidal cells throughout the hippocampus were markedly stunted in both homozygous and heterozygous Gdf5 null mutants, indicating that dendrite size and complexity are exquisitely sensitive to the level of endogenous GDF5 synthesis. © 2013. ; This work was supported by the Wellcome Trust [grant number 085984 to A.M.D.]; Proyecto de Excelencia of Regional Government Andalussia [grant number P10- CVI-6740 to A.R.-T.]; Fundação para a Ciencia e a Tecnologia [grant SFRH/BD/60498/2009 to C.O.]; and a 'Sara Borrell' Postdoctoral Fellowship from the National Institutes of Health 'Carlos III', Spain [grant number CD08/00078 to P.J.C.]. Deposited in PMC for immediate release ; Peer Reviewed