title: Heparin activates Wnt signaling for neuronal morphogenesis.
abstract: Wnt factors are secreted ligands that affect different aspects of the nervous system behavior like neurodevelopment, synaptogenesis and neurodegeneration. In different model systems, Wnt signaling has been demonstrated to be regulated by heparan sulfate proteoglycans (HSPGs). Whether HSPGs modulate Wnt signaling in the context of neuronal behavior is currently unknown. Here we demonstrate that activation of Wnt signaling with the endogenous ligand Wnt-7a results in an increased of neurite outgrowth in the neuroblastoma N2a cell line. Interestingly, heparin induces glycogen synthase kinase-3beta (GSK-3beta) inhibition, beta-catenin stabilization and morphological differentiation in both N2a cells and in rat primary hippocampal neuronal cultures. We also show that heparin modulates Wnt-3a-induced stabilization of beta-catenin. Several extracellular matrix and membrane-attached HSPGs were found to be expressed in both in vitro neuronal models. Changes in the expression of specific HSPGs were observed upon differentiation of N2a cells. Taken together, our findings suggest that HSPGs may modulate canonical Wnt signaling for neuronal morphogenesis.
authors.affiliation: Centro de Regulación Celular y Patología Joaquín V. Luco, MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Marcela
authors.initials: M
authors.lastname: Colombres
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Henríquez
authors.forename: Germán F
authors.initials: GF
authors.lastname: Reig
authors.forename: Jessica
authors.initials: J
authors.lastname: Scheu
authors.forename: Rosario
authors.initials: R
authors.lastname: Calderón
authors.forename: Alejandra
authors.initials: A
authors.lastname: Alvarez
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D048430:Cell Shape; D055513:Connective Tissue Growth Factor; D006023:Glycoproteins / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006493:Heparin / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
chemical_list: D055513:Connective Tissue Growth Factor; D006023:Glycoproteins; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat