Bone morphogenetic protein-7 stimulates initial dendritic growth in sympathetic neurons through an intracellular fibroblast growth factor signaling pathway

Abstract

Bone morphogenetic protein-7 (BMP-7), a member of the transforming growth factor (TGF)-beta superfamily of signaling cytokines, induces dendritic growth in rat sympathetic neurons. In this study, we present evidence that the recently discovered integrative nuclear FGFR1 signaling (INFS) pathway is involved in dendrite outgrowth mediated by BMP-7. Immunocytochemical analysis of expressed fibroblast growth factors (FGFs) showed that little FGF-2 was detected in control neurons, but the expression of this molecule in the cytoplasm and nucleus increased within 6 h after BMP-7 treatment. In contrast, FGF-1 was constitutively present in the peripheral cytoplasm and in neurites under control conditions, and its distribution did not change with BMP-7 exposure. The high-affinity receptor FGFR1 was present in low amounts in control neurons and was associated with the cytoplasm, the plasma membrane, and the nucleus. Twenty-four hours of BMP-7 treatment elicited an increase in FGFR1 nuclear localization. Overexpressed constructs of FGFR1 that lack the tyrosine kinase domain, and have been shown to act in a dominant-negative manner on FGFR1 signaling, inhibited BMP-7 mediated initial dendrite outgrowth in transfected neurons by approximately 50%. However, targeted inhibition of extracellular FGF-2 by overexpression of a secreted receptor mutant FGFR1(TM-) lacking the transmembrane domain failed to affect BMP-7 induced dendritic growth, as did treatment with the extracellular FGFR antagonist inositol hexakisphosphate. These results suggest that the INFS, which has already been implicated in a broad range of activities in other cell types, may also be required for BMP-7 to stimulate dendritic development.